The drug discovery process is a complex and time-consuming endeavor that can greatly benefit from advancements in computational biology. This study explores the implementation of GPU-accelerated computational methods to enhance molecular docking simulations and virtual screening techniques, two crucial components of drug discovery. By leveraging the parallel processing capabilities of Graphics Processing Units (GPUs), we significantly accelerate the analysis of protein-ligand interactions and the identification of potential lead compounds. Our approach utilizes optimized algorithms and software frameworks to achieve substantial speedups over traditional CPU-based methods. Results demonstrate that GPU-accelerated molecular docking simulations and virtual screening can reduce computation times by up to 10-fold, enabling rapid and accurate identification of promising drug candidates. This accelerated workflow has the potential to revolutionize the drug discovery pipeline, facilitating the development of novel therapeutics and reducing the time and cost associated with bringing new treatments to market.

An important parameter in the development of a new drug is the drug's affinity to the identified target (protein/enzyme). Predicting the ligand binding to the target (protein/enzyme) by molecular simulation would allow the synthesis to be restricted to the most promising compounds.A restricted hybrid HF-DFT calculation was performed in order to obtain the most stable conformer of each ligand and a series of DFT calculations using the B3LYP levels with 6-31G* basis set has been conducted. The docking studies of the quinolone compounds will be performed with the CLC Drug Discovery Workbench to identify and visualize the ligand-receptor interaction mode.

Infection-related cardiovascular diseases (CVDs) represent a significant health challenge, necessitating novel therapeutic strategies targeting key receptors involved in inflammation and infection. Antimicrobial peptides (AMPs) offer a promising approach, potentially disrupting pathogenic processes. This study aimed to investigate the efficacy of AMPs as therapeutic agents by examining their interactions with critical CVD-related receptors. A comprehensive computational approach was utilized to assess the interactions between AMPs and receptors associated with CVDs. Molecular docking studies were conducted to evaluate AMP binding to target receptors: ACE2, CRP, MMP9, NLRP3, and TLR4. The top-performing AMPs were further analyzed through 100 ns molecular dynamics (MD) simulations, and their binding affinities were quantified using MM/PBSA calculations. The analysis revealed that Tachystatin, Pleurocidin, and Subtilisin A exhibit strong binding affinities to key CVD-related receptors, including ACE2, CRP, and MMP9. These AMPs demonstrated the potential for disrupting receptor-peptide interactions critical to infection and inflammation. MD simulations confirmed the stability of AMP-receptor complexes, with MM/PBSA calculations showing significant binding energies. Future directions include conducting in vitro and in vivo studies to validate the therapeutic efficacy and safety of these AMPs in clinical settings.

Polymers' controlled pyrolysis is an economical and environmentally friendly solution to prepare activated carbon. However, due to the experimental difficulty in measuring the dependence between tissues and pyrolysis parameters at high temperatures, the unknown pyrolysis mechanism hinders access to the target products with desirable morphologies and performances. In this study, we investigate the pyrolysis process of polystyrene under different heating rates and temperatures employing reactive molecular dynamics (ReaxFF-MD) simulations. A clear profile of the generation of pyrolysis products determined by the temperature and heating rate is constructed. It is found that the heating rate affects the type and amount of pyrolysis intermediates and their timing, and low-rate heating helps yield more diverse pyrolysis intermediates. While the temperature affects the pyrolytic tissues of the final equilibrium products, either too low or too high a target temperature is detrimental to generating large areas of graphitized tissue. The established theoretical evolution process matches experiments well, thus contributing to preparing target activated carbons by referring to the regulatory mechanism of pyrolytic tissues.

Computational modeling (CM) is a versatile scientific methodology used to examine the properties and behavior of complex systems, such as polymeric materials for biomedical bioengineering. CM has emerged as a primary tool for predicting, setting up, and interpreting experimental results. Integrating in silico and in vitro experiments accelerates scientific advancements, yielding quicker results at a reduced cost. While CM is a mature discipline, its recent prominence in Bio-medical Engineering for biopolymer materials has recently gained prominence. In biopolymer biomedical engineering, CM focuses on three key research areas: A) Computer-aided design (CAD/CAM), B) Finite Element Analysis, and C) Molecular Dynamic Simulations. This review centers on Molecular Dynamics (MD) simulations in biopolymers, analyzing structural, functional, and evolutionary aspects of biomolecular systems over time. MD simulations solve Newton's equations of motion for all-atom systems, generating spatial trajectories for each atom, providing insights into properties like water absorption on biopolymer surfaces and interactions with solid surfaces, crucial for biomaterial assessment. This review offers readers a comprehensive overview of the diverse applications of Molecular Dynamics (MD) simulations on biopolymers. Furthermore, it emphasizes the flexibility, robustness, and synergistic relationship between in silico and experimental techniques.

Eukaryotic cells contain membranes with various curvatures, from the near-plane plasma membrane to the highly curved membranes of organelles, vesicles, and membrane protrusions. These curvatures are generated and sustained by curvature-inducing proteins, peptides, and lipids, and describing these mechanisms is an important scientific challenge. In addition to that, some molecules can sense membrane curvature and a thereby be trafficked to specific locations. The description of curvature-sensing is another fundamental challenge. Curved lipid membranes and their interplay with membrane-associated proteins can be investigated with molecular dynamics (MD) simulations, given the right tools. Various methods for simulating curved membranes with MD are discussed here, including tools for setting up simulation of vesicles, and methods for sustaining membrane curvature. The latter are divided into methods that exploit scaffolding virtual beads, methods that use curvature-inducing molecules, and methods applying virtual forces. The variety of simulation tools allow the researcher to closely match the conditions of experimental studies of membrane curvatures.

Natural products from plants such as, chemopreventive agents attract huge attention because of their low toxicity and high specificity. The rational drug design in combination with structure based modeling and rapid screening methods offer significant potential for identifying and developing lead anticancer molecules. Thus, the molecular docking method plays an important role in screening a large set of molecules based on their free binding energies and proposes structural hypotheses of how the molecules can inhibit the target. Several peptide based therapeutics have been developed to combat several health disorders including cancers, metabolic disorders, heart-related, and infectious diseases. Despite the discovery of hundreds of such therapeutic peptides however, only few peptide-based drugs have made it to the market. Moreover, until date the activities of cyclic peptides towards molecular targets such as protein kinases, proteases, and apoptosis related proteins have never been explored. In this study we explore the in silico kinase and protease inhibitor potentials of cyclosaplin as well as study the interactions of cyclosaplin with other cancer-related proteins. Previously, the structure of cyclosaplin was elucidated by molecular modeling associated with dynamics that was used in the current study. Docking studies showed strong affinity of cyclosaplin towards cancer-related proteins. The binding affinity closer to 10 indicated efficient binding. Cyclosaplin showed strong binding affinities towards protein kinases such as EGFR, VEGFR2, PKB and p38 indicating its potential role in protein kinase inhibition. Moreover, it displayed strong binding affinity to apoptosis related proteins and revealed the possible role of cyclosaplin in apoptotic cell death. The protein-ligand interactions using LigPlot displayed some similar interactions between cyclosaplin and peptide-based ligands especially in case of protein kinases and a few apoptosis related proteins. Thus, the in silico analyses gave an insight of cyclosaplin as a potential apoptosis inducer and protein kinase inhibitor.

The novel coronavirus disease 19 (COVID-19) has resulted in an estimated 20 million excess deaths and the recent resurgence of COVID-19 in China is predicted to result in up to 1 million deaths over the next few months. With vaccines unable to halt transmission it is important to continue our quest for safe, effective, affordable drugs that will be available to all countries. Drug repurposing is one of the strategies being explored in this context. Recently, out of 7,817 approved drugs, 214 candidates were systematically down-selected using a combination of 11 filters including approval status, assay data against SARS-CoV-2, pharmacokinetic, pharmacodynamic and toxicity profiles. These drugs were subjected in this study to virtual screening against various targets of SARS-CoV-2 followed by molecular dynamic studies of the best scoring ligands against each target. The chosen molecular targets were Spike receptor binding domain, Nucleocapsid protein RNA binding domain, and key non-structural proteins 3, 5, 12, 13 and 14. Four drugs approved for other indications — alendronate, cromolyn, natamycin and treprostinil — look sufficiently promising from our in silicostudies to warrant further in vitro and in vivo investigations as appropriate to ascertain their extent of anti-viral activities.

In this study, we investigate the structural changes, electronic properties, and charge redistribution within azo-bithiophene (Azo-BT) chemisorbed monolayers under different light stimuli using density functional theory and molecular dynamics simulations. We consider two types of switches, Azo-BT and BT-Azo, with different arrangements of the Azo and BT blocks counting from the anchor thiol group. The chemisorbed monolayers of pure cis- and trans-isomers with a surface concentration of approximately 2.7 molecules per nm2 are modeled on a gold surface using classical all-atom molecular dynamics. Our results reveal significant shrinkage of the BT-Azo layer under UV illumination, whereas the thicknesses of the Azo-BT layer remain comparable for both isomers. This difference in behavior is attributed to the ordering of the trans-molecules in the layers, which is more pronounced for Azo-BT, leading to a narrow distribution of the inclination angle to the gold surface. Conversely, both layers consisting of cis-switches exhibit disorder, resulting in similar brush heights. To study charge transfer within the immobilized layers, we analyze each snapshot of the layer and calculate mean charge transfer integrals using Nelsen’s algorithm for a number of interacting neighboring molecules. Combining these integrals with reorganization energies defined for the isolated molecules, we evaluate the charge transfer rates and mobilities for electron and hole hopping within the layers at room temperature based on Marcus’ theory. This research offers new perspectives for the innovative design of electrode surface modifications and provides insights into controlling charge transfer within immobilized layers using light triggers. Additionally, we identify molecular properties that are enhanced through specific molecular design, which contributes to the development of more efficient molecular switches for various electronic applications.

The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral Integrase (IN) enzyme catalyses integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG) and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of Integrase Strand Transfer Inhibitors (INSTIs). In this study, we applied computational methods of molecular modelling and docking to analyse the effect of NOPs on the full-length IN structure and INSTI binding. We identified 16 NOPs within the Cameroonian derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any effect on INSTI binding. INSTIs displayed similar binding affinities to each IN structure. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment naïve populations. This study supports the use of second-generation INSTI DTG as part of first-line combination antiretroviral therapy (cART) regimens, due to DTG possessing a stronger genetic barrier to the emergence of drug resistance.

In this work, a tool for estimating the contact angle from the molecular dynamics simulations is developed and presented. The tool (Achilles) can detect water droplet on hydrophobic and hydrophilic surfaces. The tool can reconstruct the droplets broken across the periodic boundaries. Further a neighbor density based accurate filter is used to find the droplet liquid vapor interface and a circle is fitted using it after removing the dense layers of water next to solid surface. This fitted circle is solved for contact angle and results are outputted in the form of graphical images and text. The entire content of the internal computations of the tool is broken down into 4 phases and users can monitor the outcomes at every phase through output images. The tool is tested using sample molecular dynamics results of water droplet on hydrophobic and hydrophilic surfaces. We believe this tool can be a good addition to the molecular dynamics simulation community who work on the interfacial physics, droplet evaporation, super hydrophobic surfaces, and wettability etc.

Some α-Pyrone derivatives isolated from Alternaria phragmospora fungus showed promising anti leukemic activities, while others were inactive. CRM1/XPO1 (chromosome region maintenance 1 protein, also called exportin1 or PO1 in humans) has been chosen as a target for antileukemic molecular docking study for those compounds to understand their modes of interaction and structure activity relationships. The results showed that two (2 and 4), out of six, natural α-Pyrone derivatives exhibited well-established interactions with the amino acids of the receptor, which was in agreement with the experimental anti-leukemic results of these compounds. Moreover, twenty hypothetical chemically modified α-Pyrone derivatives (7-27) have been designed. Compounds 7, 8, 22 and 24 showed more efficient docking properties than the previously considered natural compounds.

Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative and antineoplastic activities. Recently, different studies have shown that flavonoid have the potential to inhibit BET bromodomains. Previous reports suggest that flavonoids are putative inhibitors of the ZA channel due to their orientation and interactions with P86, V87, L92, L94 and N140. Herein, a comprehensive characterization of the binding mode of the biflavonoid amentoflavone and fisetin is discussed. To this end, both compounds were docked with BRD4 using four docking programs. Results were post-processed with protein-ligand interaction fingerprints. To gain further insights into the binding mode of the two natural products, docking results were further analyzed with molecular dynamics. Results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as basis for scaffold optimization and further characterization of flavonoids as BET inhibitors.

The global pandemic caused by the new SARS-COV-2 coronavirus makes it necessary to search for drugs for its control. Within of this research it has been known that the ivermectin drug, a FDA-approved drugs which is formulated as an 80:20 mixture of ivermectin B1a and B1b and used commonly for parasitic infections, has an inhibitory effect on viruses, includes SARS-COV-2 at in vitro level. In the particular case of SARS-COV-2 its mechanism of action remains elusive and controversial. Interestingly, the energy of interaction of ivermectin with any of the proteins the SARS-CoV-2 and the possible structural alterations at the protein level that this drug can cause have not been reported. In this sense, we carried out a bioinformatics study with docking strategies and molecular dynamics to predict the binding and disturbance induced by ivermectin in proteins associated with SARS-CoV-2. We use DockThor and Molegro docking scores. The DockThor server and myPresto software were used to build complexes and dynamics studies, respectively. The results obtained suggested that ivermectin is capable of docking with the 3CL protease and the HR2 domain, and may promote structural changes in these proteins by inducing unfolding/folding. Specifically, ivermectin brings protease to a significantly more deployed conformational state and the HR2 domain to a more compact state compared to the native state. Finally, it is shown that B1a and B1b macrocyclic lactones have a behavior different from to each target protein. These results suggest a possible inhibitory effect against SARS-CoV-2 due to a synergistic role of this drug to spontaneously bind to two important proteins involve in the proliferation of this virus. However, more studies are required on this possible mechanism of action.

Histone Lysine Specific Demethylase 1 (LSD1) is overexpressed in many cancers and become a new target for anticancer drugs. In recent years, the small molecule inhibitors with various structures targeting LSD1 have been reported. Here we report the binding interaction modes of a series of thieno[3,2-b]pyrrole-5-carboxamides LSD1 inhibitors using molecular docking, three dimensional quantitative structure-activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA q²=0.783, r²=0.944, r²_pred=0.851) and Comparative molecular similarity indices analysis (CoMSIA q²=0.728, r²=0.982, r²_pred=0.814) were used to establish 3D-QSAR models, which had good verification and prediction capabilities. Based on the contour maps and the information of molecular docking, 8 novel small molecules were designed in silico, among which compounds D4, D5 and D8 with high predictive activity were subjected to further molecular dynamics simulations (MD), and their possible binding modes were explored. It was found that Asn535 plays a crucial role in stabilizing the inhibitors. Furthermore, the ADME and bioavailability prediction for D4, D5 and D8 were carried out. The results would provide valuable guidance for designing new reversible LSD1 inhibitors in the future.

Deep eutectic solvents (DESs) are one of the most rapidly evolving types of solvents, appearing in a broad range of applications such as nanotechnology, electrochemistry, biomass transformation, pharmaceuticals, membrane technology, biocomposite development, modern 3D-printing, and many others. The range of their applicability continues to expand, which demands the development of new DESs with improved properties. To do so requires an understanding of the fundamental relationship between the structure and properties of DESs. Computer simulation and machine learning techniques provide a fruitful approach as they can provide predictions, reveal physical mechanisms and readily be linked to experiments. This review is devoted to the computational research of DESs and describes technical features of DES simulations and the corresponding perspectives on various DES applications. The aim is to demonstrate the current frontiers of computational research of DESs and discuss future perspectives.

Prototype of a family of at least nine members, c-src tyrosine kinase is a therapeutically interesting target, because its inhibition might be of interest not only in a number of malignancies, but also in a diverse array of conditions, from neurodegenerative pathologies to certain viral infections. Computational methods in drug discovery are considerably cheaper than conventional methods and offer opportunities of screening very large numbers of compounds in conditions that would be simply impossible within the wet lab experimental settings. We have explored the use of global QSAR models and molecular ligand docking in the discovery of new c-src tyrosine kinase inhibitors. Using a data set of 1038 compounds from ChEMBL and 19 blocks of molecular descriptors, we have developed over 200 QSAR classification models, based on six machine learning algorithms and 17 feature selection methods. We have selected 49 with reasonably good performance (positive predictive value and balanced accuracy higher than 70% in nested cross validation) and the models were assembled by stacking with a simple majority vote and used for the virtual screening of over the “named” ZINC data set (over 100,000 compounds). 744 compounds were predicted by at least 50% of the QSAR models as active, 147 compounds were within the applicability domain and predicted by at least 75% of the models to be active. The latter 147 compounds were submitted to molecular ligand docking using Vina and Ledock, and a number of 90 were predicted to be active based on the binding energy. External data from CHEMBL and PUBCHEM confirmed that at least 7.83% (in the case of QSAR) or 6.67% (in the case of integrated QSAR and molecular docking) of the compounds are active on the c-src target.

Histones are keys to many epigenetic events and their complexes have therapeutic and diagnostic importance. The determination of the structures of histone complexes is fundamental in the design of new drugs. Computational molecular docking is widely used for the prediction of target-ligand complexes. Large, linear peptides like the tail regions of histones are challenging ligands for docking due to their large conformational flexibility, extensive hydration, and weak interactions with the shallow binding pockets of their reader proteins. Thus, fast docking methods often fail to produce complex structures of such peptide ligands at a level appropriate for drug design. To answer this challenge, and improve the structural quality of the docked complexes, post-docking refinement has been applied using various molecular dynamics (MD) approaches. However, a final consensus has not been reached on the desired MD refinement protocol. In the present study, MD refinement strategies were systematically explored on a set of problematic complexes of histone peptide ligands with relatively large errors in their docked geometries. Six protocols were compared that differ in their MD simulation parameters. In all cases, pre-MD hydration of the complex interface regions was applied to avoid the unwanted presence of empty cavities. The best-performing protocol achieved a median of 32 % improvement over the docked structures in terms of the change of root mean squared deviations from the experimental references. The influence of structural factors and explicit hydration on the performance of post-docking MD refinements was also discussed to help their implementation in future methods and applications.

G protein-coupled receptors (GPCRs) are critical drug targets. GPCRs convey signals from the extracellular to the intracellular environment through G proteins. There is evidence that some ligands that bind to the GPCRs activate different downstream signaling pathways. G protein activation or -arrestin biased signaling involves ligands binding to receptors and stabilizing conformations that trigger a specific pathway. Molecular dynamics (MD) simulations are especially valuable for obtaining detailed mechanistic information, including identification of allosteric sites and understanding modulators' interactions between receptors and ligands. Here, we highlight recent simulation studies and methods used to study biased G protein-coupled receptor signaling and their conformational dynamics. We also highlight applications of MD simulations to drug discovery.

We have synthesized quinoxaline analogs (1-25), characterized by 1HNMR and HREI-MS and evaluated for thymidine phosphorylase inhibition. Among the series, nineteen analogs showed better inhibition when compared with the standard inhibitor 7-Deazaxanthine (IC50 = 38.68 ± 4.42 µM). The most potent analog among the series is analog 25 with IC50 value 3.20 ± 0.10 µM. Sixteen analogs 1, 2, 3, 4, 5, 6, 7, 12, 13, 14, 15, 16, 17, 18, 21and 24 showed outstanding inhibition which is many folds better than the standard 7-Deazaxanthine. Two analogs 8 and 9 showed moderate inhibition. A structure- activity relationship has been established mainly based upon the substitution pattern on the phenyl ring. The binding interactions of the active compounds were confirmed through molecular docking studies.

A sedentary lifestyle associated with unregulated diets rich in high-calorie foods have contributed to the great prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) latterly, with up to 60% in high-risk population and 25% in the general population. The absence of specific pharmacological strategies for this syndrome represents one of the major problems in the management of MASLD patients. Lifestyle interventions and adherence to a healthy diet are the main cornerstones of current therapies. The identification of nutraceuticals useful in the treatment of MASLD appears to be one of the most promising strategies for the development of new effective and safe treatments for this disease. The onion, one of the most widely studied foods in the field of nutraceuticals, serves as an inexhaustible reservoir of potent compounds with various beneficial effects. The following preliminary study analyses, mediating in silico studies, the iteration of a library of typical onion compounds with 3-hydroxy-3-methylglutaryl-coenzyme A reductase, Liver receptors X α and β as well as Peroxisome proliferator-activated receptors α and γ. In this study fort the first time promising smart molecules from the onion that could have a beneficial action in MASLD patients were identified.

Indole derivatives are key components of natural products and possesses a wide range of biological and pharmaceutical applications. Here we present the synthesis of a new indole derivative namely 2-(1-ethyl-5-nitro-1H-indole-7-carbonyl) butyl 4-methylbenzenesulfonate (5). The structural elucidation of 5 was accomplished through comprehensive spectroscopic analysis, including Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and high-resolution mass spectrometry (HRMS). Our molecular docking study revealed that compound 5 exhibits strong affinity towards Tyrosinase, making it a promising candidate as an antioxidant agent. Keywords: Indole derivative; Tosyl group; Molecular docking; Antioxidant agent.

Molecular Dynamics (MD) simulations model motion of molecules in atomistic detail and aid in drug design. While simulations on large systems may require several days to complete, analysis of terabytes of data generated in the process could also be time consuming. Recent studies captured exciting and dramatic drug-receptor interactions under cell-like complex conditions. Such advances make simulations of biomolecular interactions more realistic, insightful, and informative and have potential to make drug design more realistic. However, currently available resources and techniques do not provide, in reasonable time, a comprehensive understanding of events seen in simulations. We demonstrate that big data approach results in significant speedups, and provides rapid insights into simulations performed. Advancing this improvement, we propose a scalable, self-tuning, and responsive framework based on Cloud-infrastructure to accomplish the best possible MD studies with given priorities and within available resources.

Aurora kinase A (AURKA) is a normal cell proliferation-inducing enzyme encoded by AURKA gene, with over-expression observed in different types of malignancies. Hence, the goal is to find potential inhibitors against AURKA. In this study, molecular docking, Standard Precision and Extra Precision methods were employed. After the docking study, the ligands showed an extremely low binding score which suggested very high binding affinity of the ligands. Furthermore, Quantum polarized ligand docking (QPLD) was performed to predict the binding status of the molecules. Based on the binding affinity, the top four compounds were chosen for further analysis. The docked complexes were further analyzed in explicit water conditions using 100 ns molecular dynamics simulations and binding free energy calculation. Then, density functional theory (DFT) calculation was used to calculate the molecular properties of the molecules. Finally, systems biology experiments validated the molecular docking and molecular dynamics simulation studies and indicated that quercetin, kaempferol, luteolin and rutin could inhibit the AURKA. The results show that, these four molecules have high binding affinity to the AURKA and significant interactions (LEU139, GLU211and ALA213) were also identified with the hinge region of Aurora kinase A. Thus, LEU139, GLU211, and ALA213 were identified as the crucial protein mechanisms.

Zika virus (ZIKV) has been characterized as one of the potential pathogens and placed under future epidemic outbreaks by the WHO. However, lack of potential therapeutics can result in uncontrolled pandemic like other human pandemic viruses; therefore, prioritized effective therapeutics development has been recommended against ZIKV. In this context, the present study adopted the strategy to explore the lead compounds from Azadirachta indica against ZIKV via concurrent inhibition of the ZIKVpro and ZIKVRdRp proteins using molecular simulations. Initially, structure-based virtual screening of 44 bioflavonoids reported in Azadirachta indica against the crystal structures of targeted ZIKV proteins resulted in the identification of top four common bioflavonoids, viz. rutin, nicotiflorin, isoquercitrin, and hyperoside. These compounds showed substantial docking energy (-7.9 to -11.01 kcal/mol) and intermolecular interactions with essential residues of ZIKVpro (His51, Asp74, and Ser135) and ZIKVRdRp (Asp540, Ile799, and Asp665) by comparison to the reference compounds, O7N inhibitor (ZIKVpro) and Sofosbuvir inhibitor (ZIKVRdRp). Long interval molecular dynamics simulation (500 ns) on the selected docked poses reveals the stability of respective docked complexes contributed by intermolecular hydrogen bonds and hydrophobic interactions. The predicted complex stability was further supported by calculated end-point binding free energy using molecular mechanics generalized born surface area (MM/GBSA) method. Consequently, the identified common bioflavonoids are recommended as promising therapeutic inhibitors of ZIKVpro and ZIKVRdRp for further experimental assessment.

In the search of potent α-amylase inhibitors, we have synthesized seventeen derivatives of 2-mercaptobenzimidazole bearing sulfonamide (1-17) and evaluated for their α-amylase inhibitory potential. All compounds display a variable degree of α-amylase activity having IC50 values ranging between 0.90 ± 0.05 to 11.20 ± 0.30 µM when compared with the standard drug acarbose having IC50 value 1.70 ± 0.10 µM. Compound 1, 2, 11, 12 and 14 having IC50 values 1.40 ± 0.10, 1.30 ± 0.05, 0.90 ± 0.05, 1.60 ± 0.05 and 1.60 ± 0.10 µM respectively were found many folds better than the standard drug acarbose. The remaining analogs showed good inhibitory potentials. All the synthesized compounds were characterized by HREI-MS, 1H and 13C-NMR. Structure activity relationship (SAR) has been recognized for all newly synthesized analogs. Through molecular docking study, binding mode of active analogs with α-amylase enzyme was confirmed.

New class of triazinoindole bearing thiosemicarbazide (1-25) was synthesized and evaluated for α-glucosidase inhibitory potential. All synthesized analogues exhibited excellent inhibitory potential having IC50 values ranging from 1.30 ± 0.01 to 35.80 ± 0.80 µM when compared with the standard acarbose having IC50 value 38.60 ± 0.20 µM. Among series the analogues 1 and 23 was found the most potent having IC50 values 1.30 ± 0.05 and 1.30 ± 0.01 µM respectively. Structure activity relationship (SAR) was mainly based upon by bring about difference of substituents on phenyl rings. To confirm the binding interactions, molecular docking study was performed. Synthesized analogues were characterized through HREI-MS, 1H and 13C-NMR analysis.

Purification of biologically-derived therapeutics is a major cost contributor to the production of this rapidly growing class of pharmaceuticals. Monoclonal antibodies comprise a large percentage of these products therefore new antibody purification tools are needed. Small peptides, as opposed to traditional antibody affinity ligands such as Protein A, may have advantages in stability and production costs. Multiple heptapeptides that demonstrate Fc binding behavior that have been identified from a combinatorial peptide library using M13 Phage Display are presented herein. Seven unique peptide sequences of diverse hydrophobicity and charge were identified. All seven peptides showed strong binding to the four major human IgG isotypes, human IgM, as well as binding to canine, rat, and mouse IgG. These seven peptides were also shown to bind human IgG4 from DMEM cell culture media with 5% FCS and 5 g/L ovalbumin present. These peptides may be useful as surface ligands for antibody detection and purification purposes. Molecular docking and classical molecular dynamics (MD) simulations were conducted to elucidate the mechanisms and energetics for the binding of these peptides to the Fc region. The binding site was found to be located between the two glycan chains inside the Fc fragment. Both hydrogen bonding and hydrophobic interactions were found to be crucial for the binding interactions. Excellent agreement for the binding strength was obtained between experimental results and simulations.

The outbreak of novel coronavirus (COVID-19) infections in 2019 is in dire need of finding potential therapeutic agents. In this study, we used molecular docking to repurpose HIV protease inhibitors and nucleoside analogues for COVID-19, with evaluations based on docking scores calculated by AutoDock Vina and RosettaCommons. Our results suggest that Indinavir and Remdesivir possess the best docking scores, and comparison of the docking sites of the two drugs reveal a near perfect dock in the overlapping region of the protein pockets. After further investigation of the functional regions inferred from the proteins of SARS coronavirus, we discovered that Indinavir does not dock on any active sites of the protease, which may give rise to concern in regards to the efficacy of Indinavir. On the other hand, the docking site of Remdesivir is not compatible with any known functional regions, including template binding motifs, polymerization motifs and nucleoside triphosphate (NTP) binding motifs. However, when we tested the active form (CHEMBL2016761) of Remdesivir, the docking site revealed a perfect dock in the overlapping region of the NTP binding motif. This result suggests that Remdesivir could be a potential therapeutic agent. Clinical trials still must be done in order to confirm the curative effect of these drugs.

The successive steps of the oxidation mechanism of crocin, major compound of saffron, by the free OH• radical are investigated by the pulse radiolysis, steady-state (gamma) radiolysis methods and molecular simulations. The optical absorption properties of the transient species and their reaction rate constants are determined. The absorption spectrum of the oxidized radical of crocin resulting from the H-abstraction presents a maximum at 678 nm and a band at 441 nm, almost as intense as that of crocin. The spectrum of the covalent dimer of this radical contains an intense band at 441 nm and a weaker one at 330 nm. The final oxidized crocin, issued from radical disproportionation, absorbs weaker with a maximum at 330 nm. The molecular simulation results suggest that the OH• radical is electrostatically attracted by the terminal sugar and is scavenged predominantly by the neighbor methyl site of the polyene chain as in a sugar-driven mechanism. Based on detailed experimental and theoretical investigations, the antioxidant properties of crocin are highlighted.

The elderly population is particularly susceptible to myocardial damage caused by heat stress (HS). With the continuous increase in global temperatures, this poses an undeniable challenge to human health. This study aimed to investigate the therapeutic effect of Shikimic Acid (SA) in treating HS-induced myocardial damage through network pharmacology, molecular docking, molecular dynamics (MD) simulations, and in vitro experiments. Network pharmacology analysis revealed that SA alleviates the inflammatory response in the heart muscle associated with HS by targeting 60 disease-related targets, such as TP53, TNF, and IL-6. The tumor proteoglycan, the PI3K-Akt signaling pathway, and hepatitis B were identified as the primary therapeutic pathways. Molecular docking and MD simulation results confirmed that SA can stably bind to both TNF (-6.642 kcal/mol) and IL-6 (-7.261 kcal/mol), and the complexes of Shikimic Acid-IL-6 and Shikimic Acid-TNF did not undergo significant changes within 100 ns. In addition, the in vitro experiment showed that 250 μM SA significantly increased the survival rate of HL-1 cells exposed to 43°C for 2 h by 71.1% and promoted the proliferation of HL-1 cells by 30.7%. Overall, these findings provide substantial evidence for the therapeutic potential of SA in HS-induced myocardial damage.

The formation of atroposelective biaryl compounds in plants and fungi is well understood; however, the polyketide aglycone synthesis and dimerization in bacteria remain unclear. Thus, the biosynthetic gene cluster (BGC) responsible for antibacterial setomimycin production from Streptomyces nojiriensis JCM3382 was examined in comparison with the BGCs of spectomycin, julichromes, lincolnenins, and huanglongmycin. Setomimycin BGC includes post-PKS assembly/cycling enzymes StmD (C-9 ketoreductase), StmE (aromatase), and StmF (thioesterase) as key components. The heterodimeric TcmI-like cyclases StmH and StmK are proposed to aid in forming the setomimycin monomer. In addition, StmI (P-450) is predicted to catalyze biaryl coupling of two monomeric setomimycin units, with StmM (ferredoxin) specific to setomimycin BGC. The roles of StmL and StmN, part of the nuclear transport factor 2 (NTF-2)-like protein family and unique to setomimycin BGCs, could particularly interest biochemists and combinatorial biologists. α-Glucosidase, a key enzyme in type 2 diabetes, hydrolyzes carbohydrates into glucose, thereby elevating blood glucose levels. This study aimed to assess the α-glucosidase inhibitory activity of EtOAc extracts of JCM 3382 and setomimycin. The JCM 3382 EtOAc extract and setomimycin exhibited greater potency than the standard inhibitor, acarbose, with IC50 values of 285.14 ± 2.04 μg/mL and 231.26 ± 0.41 μM, respectively. Kinetic analysis revealed that setomimycin acts as a competitive inhibitor of α-glucosidase. Molecular docking demonstrated two hydrogen bonds with maltase-glucoamylase chain A residues Thr205 and Lys480 (binding energy = −6.8 kcal·mol⁻¹), two π-π interactions with Trp406 and Phe450, and one π-cation interaction with Asp542. Residue-energy analysis highlighted Trp406 and Phe450 as key in setomimycin's binding to maltase-glucoamylase. These findings suggest that setomimycin is a promising candidate for further enzymological research and potential antidiabetic therapy.

Background: COVID-19, a member of corona virus family is spreading its tentacles across the world due to lack of drugs at present. Associated with its infection are cough, fever and respiratory problems causes more than 15% mortality worldwide. It is caused by a positive, single stranded RNA virus from the enveloped coronaviruse family. However, the main viral proteinase (Mpro/3CLpro) has recently been regarded as a suitable target for drug design against SARS infection due to its vital role in polyproteins processing necessary for coronavirus reproduction.Objectives: The present in silico study was designed to evaluate the effect of Eucalyptol (1,8 cineole), a essential oil component from eucalyptus oil, on Mpro by docking study.Methods: In the present study, molecular docking studies were conducted by using 1-click dock and swiss dock tools. Protein interaction mode was calculated by Protein Interactions Calculator.Results: The calculated parameters such as RMSD, binding energy, and binding site similarity indicated effective binding of eucalyptol to COVID-19 proteinase. Active site prediction further validated the role of active site residues in ligand binding. PIC results indicated that, Mpro/eucalyptol complexes forms hydrophobic interactions, hydrogen bond interactions and strong ionic interactions.Conclusions: Therefore, eucalyptol may represent potential treatment potential to act as COVID-19 Mpro inhibitor. However, further research is necessary to investigate their potential medicinal use.

The details of antigen-antibody interactions and the identification of epitopes are critical for the development of monoclonal antibody drugs. Ab42 is a native human-derived anti-CFH monoclonal antibody. In this study, the interaction between antigen pCFH and antibody (Ab42) was theoretically demonstrated by molecular docking and MD simulation, combined with free energy calculation and computational alanine scanning (CAS), and key amino acids and epitopes were identified. Experimental alanine scanning (EAS) was then carried out to verify the results of the calculation, and our results indicated that Ab42 antibody forms hydrogen bonds and interacts hydrophobically with pCFH through the Tyr315, Ser100, Gly33, and Tyr53 residues on its CDR, while the main pCFH epitopes are located at the six sites of Pro441, Ile442, Asp443, Asn444, Ile447, and Thr448. In conclusion, this study has explored the mechanism of antigen-antibody interaction from both theoretical and experimental aspects, and our results have important theoretical significance for the design and development of relevant antibody drugs.

Curcumin, a major constituent of turmeric, has beneficial effects against several diseases. In cystic fibrosis (CF), this compound potentiates the activity of a number of cystic fibrosis transmembrane conductance regulator (CFTR) mutants. Despite holding promise in the treatment of CF, the curcumin binding site in CFTR and the molecular mechanism of activation of this channel are still unknown. The results of the study, based on docking and molecular dynamics (MD) simulations, allow to propose that curcumin binds the closed ATP-free CFTR near the NBD1/ ICl1/ICl4 interface. The bound ligand, once approached by NBD2 during transient channel opening, lays at a multiple interdomain cross point. Thereafter, curcumin can bridge NBD1 and NBD2, and also ICL1/ICL4 and ICL2/ICL3 finally tightening the same interdomain interactions that normally uphold the active conformation in the wild type ATP-bound CFTR. The proposed binding site is compatible with biochemical observations made in previous CFTR-curcumin interaction studies. These findings provide the framework for the design of novel drugs that activate CFTR mutants characterized by defects in ATP binding and/or NBD dimerization, or even lacking NBD2.

Neuromorphic computing, reconfigurable optical metamaterials operational over a wide spectral range, holographic and nonvolatile displays of extremely high resolution, integrated smart photonics and many other applications need phase-change materials (PCMs) of the next generation with better energy efficiency, wider temperature and spectral range for reliable operation compared to current flagship PCMs as Ge2Sb2Te5 or doped Sb2Te. Gallium tellurides are promising candidates to achieve the necessary requirements because of higher melting and crystallization temperatures, combined with a low switching power and fast switching rate. At the same time, Ga2Te3 and non-stoichiometric alloys appear to be atypical PCMs, characterized by regular tetrahedral structure and the absence of metavalent bonding. The sp3 gallium hybridization in cubic and amorphous Ga2Te3 is also different from conventional p-bonding in flagship PCMs, raising a question of the phase-change mechanism. Besides, gallium tellurides exhibit a number of unexpected and highly unusual phenomena as nanotectonic compression or viscosity anomaly just above melting. Using high-energy X-ray diffraction, supported by first-principles simulations, we will unravel the atomic structure of amorphous Ga2Te5 PLD films, compare it with the crystal structure of tetragonal gallium pentatelluride, and investigate electrical, optical and thermal properties of these two materials to estimate their potential for memory applications as well as for other fields.

2-Hydroxypropyl-β-cyclodextrin (HPβCD) has unique properties to enhance the stability and the solubility of low water-soluble compounds by inclusion complexation. Understanding of the structural properties of HPβCD and its derivatives based on the number of 2-hydroxypropyl (HP) substituents at the a-D-glucopyranose subunits is rather important. In this work, replica exchange molecular dynamics simulations were performed to investigate the conformational changes of single- and double-sided HP-substitution called as 6-HPβCDs and 2,6-HPβCDs, respectively. The results show that glucose subunits in both 6-HPβCDs and 2,6-HPβCDs have lower chance to flip than in βCD. Also, HP groups are occasionally blocking the hydrophobic cavity of HPβCDs, thus hindering the drug inclusion. We found that HPβCDs with high number of HP-substitutions are more likely to be blocked, while HPβCDs with double-sided HP-substitution are even more probable to be blocked. Overall, 6-HPβCDs with three and four HP-substitutions are highlighted as the most suitable structures for guest encapsulation based on our conformational analyses such as structural distortion, radius of gyration, circularity and cavity self-closure of the HPβCDs.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder marked by progressive motor and non-motor symptoms. Traditional treatments primarily manage symptoms rather than address the disease's root causes, highlighting the need for novel therapeutic approaches. Natural phytochemicals, particularly phenolic compounds, have shown potential due to their neuroprotective effects. Antiaris africana is commonly used in traditional African medicines to treat several illnesses including neurodegenerative disorders. However, its neuroprotective mechanism remains elusive. This study aimed to employ network pharmacology-based prediction to identify key targets and pathways through which A. africana exerts its effects on PD. Targets associated with Parkinsonism were identified and analyzed for interaction with compounds from A. africana. Protein-protein interaction (PPI) networks were constructed, and key hub genes were identified using Cytoscape. Functional enrichment analysis highlighted significant pathways involved in PD. Molecular docking was performed to evaluate the binding affinities of the compounds to PD-related targets. Our results reveal that compounds such as caffeic acid, chlorogenic acid, catechin, ellagic acid, epigallocatechin, gallic acid, isoquercitrin, kaempferol, quercetin, quercitrin, and rutin interact with key proteins implicated in PD, including APP, EGFR, CASP3, ESR1, AKT1, and MAPK8. Notably, rutin exhibited strong binding affinity for EGFR, and chlorogenic acid showed potential in modulating the APP pathway. These findings suggest that phenolic compounds in A. africana may exert neuroprotective effects through multiple molecular mechanisms, offering potential therapeutic strategies for PD. This study underscores the importance of integrating molecular docking and network pharmacology to elucidate the therapeutic potential of natural compounds in complex diseases like Parkinson's disease

The World Health Organization (WHO) documents malaria as one of the leading causes of high morbidity and mortality worldwide. The disease affects millions and kills thousands of people annually. Efforts to reduce the global burden of malaria have prompted WHO to recommend prevention strategies like using anti-malarial drugs. However, these strategies have been ineffective because of anti-malarial drug resistance. The only efficacious malaria treatment is Artemisinin-based Combination Therapy (ACT). However, the extended ACTs clearance times, linked to the emergence of artemisinin monotherapy resistance recorded most recently in Africa and the Great Mekong region, pose a danger to its efficacy. Therefore, better efficacious malaria drugs are required. Since P. falciparum heat shock protein 90 (PfHsp90) is a well-characterized malaria drugs target, this study uses it to discover more efficacious malaria drugs. An in-silico approach was used to discover PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria using molecular dynamics simulation (MDS) and hierarchical virtual screening. Geldanamycin (GDM), a well-known anti-PfHsp90 compound, was used to identify PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria by screening it against the ZINC database via the ZINCPHARMER web server. This virtual screening process resulted in 17 hits. These ZINCPHARMER hits were subjected to drug-likeness and pharmacokinetics properties analysis in the SwissADME web server, and 9 of them satisfied the requirements. The 9 ZINC compounds were docked with PfHsp90 using the PyRx software to understand their interactions. From the molecular docking results, ZINC09060002 (-8.2 kcal/mol), ZINC72133064 (-7.8 kcal/mol), ZINC72163401 (-7.7 kcal/mol), ZINC72358537 (-8.1 kcal/mol), and ZINC72358557 (-7.6 kcal/mol) had better binding affinities to PfHsp90 than GDM (-7.5 kcal/mol). The stability of these molecularly docked protein-inhibitor complexes was assessed through MDS using GROMACS 2022. ZINC72163401, ZINC72358537, and ZINC72358557 formed stable complexes with PfHsp90. The lead compounds were subjected to in vitro validation for their inhibitory capability. They showed promising inhibition of parasite growth with IC50 values ranging between 200 – 400 ng/ml. In this regard, the three PfHsp90 inhibitors can be used as anti-malarial drugs. However, further structural optimization studies and clinical (in vivo) tests are necessary to ascertain the antimalarial activity of these compounds in humans.

Leucyl-aminopeptidase (LAP), an important metallopeptidase, hydrolyses amino acid residues from the N-terminal of polypeptides and proteins, acting preferentially on the peptide bond formed by N- terminus leucine. A new leucyl-aminopeptidase was found in Bacillus cereus CZ. Its gene (bclap) contained a 1485 bp ORF encoding 494 amino acids with a molecular weight of 54 kDa. The bcLAP protein was successfully expressed in E. coli BL21(DE3). Optimal activity is obtained at pH 9.0 and 58°C. The bcLAP displays a moderate thermostability and an alkaline pH adaptation range. Enzymatic activity is dramatically enhanced by Ni2+. EDTA significantly inhibits the enzymatic activity, and bestatin and SDS also show strong inhibition. The three-dimensional model of bcLAP monomer and homohexamer is simulated by Phyre2 server and SWISS-MODEL server. The docking of bestatin, Leu-Trp, Asp-Trp and Ala-Ala-Gly to bcLAP is performed using AutoDock4.2.5 , respectively. Molecular docking results show that the residues Lys260, Asp265, Lys272, Asp283, Asp342, Glu344, Arg346, Gly372, His437 are involved in the hydrogen bonding with the ligands and zinc ions. There may be two nucleophilic catalytic mechanisms in bcLAP, one involving His 437 or Arg346 and the other involving His437 and Arg346. The bcLAP can hydrolyse the peptide bonds in Leu-Trp, Leu-Trp and Ala-Ala-Gly.

Introduction: Oral candidiasis is an opportunistic fungal infection, often caused by Candida albicans. One of the virulence factors of C. albicans is sterol 14a-demethylase or CYP51. Compounds of anthocyanins (ternatin, cyanin) and flavonoids (rutin, isoquercetin, kaempferol, myricetin, limocitrin) from the extract of the Clitoria ternatea (butterfly pea) plant are believed to have potential to inhibit the CYP51 virulence factor of C. albicans to suppress oral candidiasis. The purpose of this research was to investigate the interaction between the ligands of anthocyanins and flavonoids from C. ternatea (butterfly pea) with CYP51. Methods: The in silico study applied molecular docking to examine the molecular interactions (binding affinity) between the anthocyanin and flavonoid ligands of interest from C. ternatea and the CYP51 receptor of C. albicans. Results: Predicted interactions exist between the ligands of anthocyanins (ternatin, cyanin) and flavonoids (rutin, isoquercetin, kaempferol, myricetin, limocitrin) from C. ternatea and the CYP51 receptor of C. albicans. Conclusion: C. ternatea has the potential to provide anti-fungal agents that can inhibit or slow down the occurrence of oral candidiasis, as indicated by in silico studies. However, it is important to conduct additional research regarding the properties of the plant to determine the unknown aspects of its effects to the human body.

Shale gas and coalbed methane are energy sources that partly or even mainly consist of methane stored in an adsorbed state in the pores of the organic-rich rock and coal seams. In this study, the graphene nanoslit model is employed to model the nanometer slit pores in shale and coal. The Grand Canonical Monte Carlo (GCMC) and Molecular Dynamics (MD) modelling methods are used to investigate the mechanisms of adsorption and displacement of methane in the slit pore. It was found that the CVFF forcefield resulted in the largest adsorption amount, while the PCFF forcefield resulted in the least. The COMPASS and COMPASS II force fields led to similar results. As the width of the slit pore increases, the adsorption amount of gas molecules increases, and the number density profile of adsorbed methane molecules alters from a single adsorption layer to multi-adsorption layers. The minimum slit pore width at which methane molecules can penetrate the slit pore was found to be 0.7 nm. Moreover, it is demonstrated that by lowering the temperature, the adsorption rate of the methane increases since the adsorption is an exothermic process. Enhancing methane recovery was investigated by the injection of gases such as CO2 and N2 to displace the adsorbed methane. The comparison of adsorption isotherms of gas molecules provided the following order in terms of the amount of adsorption: CO2>CH4>N2.

A derivative series of 3,4-dimethoxy-β-nitrostyrene were synthesized and identified including new compound 6. The effect of antimicrobial activity of 3,4-alkyloxy modification of β-nitrostyrene was investigated. A molecular docking was also performed to obtain information about their interactions with Protein Tyrosine Phosphatase 1B (PTP1B). PTP1B containing cysteine 215 and arginine 221 as essential active residues plays a key role in signaling pathways that regulate various cell functions of microorganisms, which also act as negative regulator in signaling pathways of insulin that are involved in type 2 diabetes and other metabolic diseases. Compound 5 and 6 were the most potent as fragment of PTP1B inhibitor based on molecular docking, but compound 5 was more effective against Candida albicans. These compounds interact with serine 216 and arginine 221 residues. However, further research is needed to investigate their potential medicinal use.

A major public health emergency has been created by the COVID-19 pandemic, which is brought on by the SARS-CoV-2 virus. Due to its crucial function in viral replication, the primary protease (Mpro) of the virus is a prime target for therapeutic research. In this study, we used molecular modeling and molecular dynamics simulations to examine the potential therapeutic uses of Mpro inhibitors for the treatment of COVID-19. Using induced fit docking and molecular dynamics simulations, we confirmed the top compounds after screening a library of compounds for their ability to bind to Mpro. Simulation interaction diagrams were used to investigate protein-ligand interactions, and MM-GBSA was used to determine binding energies. The Swiss ADME server was used to predict ADME properties. According to our findings, numerous substances are strong COVID-19 medication candidates since they have excellent ADME features and high binding affinities. This work serves as a foundation for additional experimental research and drug development initiatives aimed at Mpro.

The spread of the global COVID-19 pandemic, the lack of specific treatment and the urgent situation requires use of all resources to remedy this scourge. In the present study, using molecular docking, we identify new probable inhibitors of COVID-19 by molecules from Nigella sativa L, which is highly reputed healing herb in North African societies and both Islamic and Christian traditions. The discovery of the M^pro protease structure in COVID-19 provides a great opportunity to identify potential drug candidates for treatment. Focusing on the main proteases in CoVs (3CL^pro/M^pro) (PDB ID 6LU7 and 2GTB); docking of compounds from Nigella Sativa and drugs under clinical test was performed using Molecular Operating Environment software (MOE). Nigelledine docked into 6LU7 active site gives energy complex about -6.29734373 Kcal/mol which is close to the energy score given by chloroquine (-6.2930522 Kcal/mol) and better than energy score given by hydroxychloroquine (-5.57386112 Kcal/mol) and favipiravir (-4.23310471 kcal/mol). Docking into 2GTB active site showed that α- Hederin gives energy score about-6.50204802 kcal/mol whcih is better energy score given by chloroquine (-6.20844936 kcal/mol), hydroxychloroquine (-5.51465893 kcal/mol)) and favipiravir (-4.12183571kcal/mol). Nigellidine and α- Hederin appeared to have the best potential to act as COVID-19 treatment. Further, researches are necessary to testify medicinal use of identified and to encourage preventive use of Nigella Sativa against coronavirus infection.

Phenol is added to acetophenone (methyl phenyl ketone) and to six of its halogenated derivatives in a supersonic jet expansion to determine the hydrogen bonding preference of the cold and isolated 1:1 complexes by linear infrared spectroscopy. Halogenation is found to have a pronounced effect on the docking site in this intermolecular ketone balance experiment. The spectra unambiguously decide between competing variants of phenyl group stacking due to their differences in hydrogen bond strength. Structures where the phenyl group interaction strongly distorts the hydrogen bond are more difficult to quantify in the experiment. For unsubstituted acetophenone, phenol clearly prefers the methyl side despite a predicted sub-kJ/mol advantage which is nearly independent of zero point vibrational energy, turning this complex into a challenging benchmark system for electronic structure methods which include long range dispersion interactions in some way.

Molecular dynamics simulation is currently the theoretical technique eligible to simulate a wide range of systems from soft condensed matter to biological systems. However, of the excellent results that the technique has arrogated, this approach remains computationally expensive, but with the emergence of the new supercomputing technologies bases on graphics processing units graphical processing units-based systems GPUs, the perspective has changed. The GPUs allow performing large and complex simulations at a significantly reduced time. In this work, we present recent innovations in the acceleration of molecular dynamics in GPUs to simulate non-Hamiltonian systems. In particular, we show the performance of measure-preserving geometric integrator in the canonical ensemble, that is, at constant temperature. We provide a validation and performance evaluation of the code by calculating the thermodynamic properties of a Lennard-Jones fluid. Our results are in excellent agreement with reported data reported from literature, which were calculated with CPUs. The scope and limitations for performing simulations of high-throughput MD under rigorous statistical thermodynamics in the canonical ensemble are discussed and analyzed.

The β-amyloid cleaving enzyme 1 (BACE1) is regarded as an important target of drug design toward treatment of Alzheimer's disease (AD). In this study, three separate molecular dynamics (MD) simulations and calculations of binding free energies were carried out to comparatively probe identification mechanism of BACE1 on three inhibitors 60W, 954 and 60X. The analyses on MD trajectories indicate that the presence of three inhibitors influences structural stability, flexibility and internal dynamics of BACE1. Binding free energies calculated by using solvated interaction energy (SIE) and molecular mechanics generalized Born surface area (MM-GBSA) methods reveal that the hydrophobic interactions provide decisive forces for inhibitor-BACE1 binding. The calculations of residue-based free energy decomposition suggest that the sidechains of residues L91, D93, S96, V130, Q134, W137, F169 and I179 play key roles in inhibitor-BACE1 binding, which provides a direction for future drug design toward treatment of AD.

SOCS2, an E3 ubiquitin ligase, regulates the JAK/STAT signaling pathway, essential for cytokine signaling and immune responses. Its dysregulation contributes to cardiovascular diseases (CVDs) by promoting abnormal cell growth, inflammation, and resistance to cell death. This study aimed to elucidate the molecular mechanisms underlying the interactions between Lumbricus-derived proteins and peptides and SOCS2, with a focus on identifying potential therapeutic candidates for CVDs. Utilizing a multifaceted approach, advanced computational methodologies, including 3D structure modeling, protein-protein docking, 100 ns molecular dynamics (MD) simulations, and MM/PBSA calculations, were employed to assess the binding affinities and functional implications of Lumbricus-derived proteins on SOCS2 activity. The findings revealed that certain proteins, such as Lumbricin, Chemoattractive glycoprotein ES20, and Lumbrokinase-7T1, exhibited similar activities to standard antagonists in modulating SOCS2 activity. Furthermore, MM/PBSA calculations were employed to assess the binding free energies of these proteins with SOCS2. Specifically, Lumbricin exhibited an average ΔGbinding of -59.25 kcal/mol, Chemoattractive glycoprotein ES20 showed -55.02 kcal/mol, and Lumbrokinase-7T1 displayed -69.28 kcal/mol. These values suggest strong binding affinities between these proteins and SOCS2, reinforcing their potential therapeutic efficacy in cardiovascular diseases. Further in vitro and animal studies are recommended to validate these findings and explore broader applications of Lumbricus-derived proteins.

The outbreak of Coronavirus, as well as its emerging potential consequences, has become a global challenge worldwide, demanding effective and controlled therapeutic strategies. Potential drug candidates could achieve that with minimal toxicity. The current investigation selected 2-Deoxy-D-glucose prescribed by Defense Research and Development Organization (DRDO), India. The derivative and modified form was tested through in silico analysis against COVID-19 main protease complex with N3 inhibitor. The derived form of 2-Deoxy-D-glucose was generated by replacing the hydroxy group with a hydrogen atom, and Cypate 2-Deoxy-D-glucose was chosen as a derivative against the COVID-19 main protease complex. A molecular docking approach was adopted to identify the stable and competent form among the modified and derivative forms of 2-Deoxy-D-glucose based on binding energy. By further promoting the stabilized complex, these compounds' toxicity was also scrutinized through ADMET analysis to predict the potential candidate. The current investigation suggested that the modified version of 2-Deoxy-D-glucose was more stable with minimal toxicity against COVID-19 main protease.

Corona Virus Infectious Disease-2019 (COVID-19) outbreak originated recently at Wuhan, China in December 2019. It has already spread rapidly to more than 200 countries and has been declared a pandemic by WHO. It is caused by a beta-coronavirus named as SARS-CoV-2. There is no definitive cure, either drug or vaccine, to treat or prevent this viral disease. Recently, the crystal structure of the main protease M^pro has been determined. M^pro is responsible for the proteolytic maturation of the polyprotein essential for the viral replication and transcription, which makes it an important drug target. The discovery of new drug molecules may take years before getting to the clinics. So, considering urgency we performed molecular docking studies using FDA approved drugs to identify molecules that could potentially bind to the substrate-binding site and inhibit SARS-CoV-2 main protease (M^pro). We used the Glide module in Schrodinger software suite to perform molecular docking studies followed by MM-GBSA based energy calculations to score the hit molecules. Molecular docking and manual analysis suggest that several drugs may bind and potentially inhibit M^pro. We also performed molecular simulations studies for selected compounds to evaluate protein-drug interactions. Interestingly, we observed only one antiviral compound, Adefovir, in the top50 list of compounds. Considering bioavailability, lesser toxicity, route of administration some of the top-ranked drugs including lumefantrine (antimalarial), dipyridamole (coronary vasodilator), dihydroergotamine (used for treating migraine), hexoprenaline (anti- asthmatic), riboflavin (vitamin B2) and pantethine (vitamin B5) may be taken forward for further in vitro and in vivo experiments to investigate their therapeutic potential.

The article describes facile one-pot, hi-yielding reactions to synthesize substituted 3,4-dimethyl-1H-pyrrole-2-carboxamide (3a–m) and carbohydrazide analogues (5a–l) as potential antifungal and antimicrobial agents. The structural integrity and purity of the synthesized compounds were assigned based on appropriate spectroscopic techniques. Synthesized compounds were assessed in vitro for antifungal and antibacterial activity. The compound 5h, 5i and 5j were found to be the most potent against A. fumigatus, with MIC value of 0.031 mg/mL. The compound 5f bearing a 2,6-dichloro group on the phenyl ring was found to be the most active broad spectrum antibacterial agent with MIC value of 0.039 mg/mL. The mode of action of the most promising antifungal compounds (one representative from each series; 3j and 5h) was established by their molecular docking to the active site of sterol 14α-demethylase. Molecular docking studies revealed a highly spontaneous binding ability of the tested compounds in the access channel away from catalytic heme iron of the enzyme, which suggested that the tested compounds inhibit this enzyme and would avoid heme iron related deleterious side effects observed with existing antifungal compounds.

Based on screening in computational biology and biological in vitro assays, five natural products isolated from extracts of the herbal medicine toad skin, such as cinobufagin (CBFi), bufalin (BFi), arenobufagin (ABFi), telocinobufagin (TBFi), bufotalin (BFTi), were subjected to molecular docking calculations with the use of SARS-CoV-2 main protease (PDB 6LU7 and 7BTF) and top-scoring ligand-receptor complexes were obtained. The results showed that the binding energy of ABFi to the 3CL protein was -17.044kcal/mol, which was higher than CBFi and TBFi. However, the binding energy of ABFi to the RdRp protease was -23.250 kcal/mol, which was much lower than that of CBFi and TBFi, EVEN lower than that of ABFi to the 3CL protein. ABFi also has polar interactions with amino acids such as Glu811, Ser814, Ser681 and Thr680 of RdRp enzyme. The results revealed that ABFi had a moderate inhibitory effect on the cell proliferation of SARS-CoV-2 in vitro, with an inhibition rate of 61.12%, even weaker than Remdesivir. This new discovery provides us with new ideas for in-depth studies on the development of natural products with this class of structural generalizations as inhibitors of SARS-CoV-2, and provides an experimental basis for the next step of mechanistic studies.

Shut-in after fracturing is generally adopted for wells in shale oil reservoirs, and imbibition occurring in matrix nanopores has been proven as an effective way to improve recovery. In this research, the molecular dynamics (MD) simulation was used to investigate the effects of wettability and pressure on nanopores imbibition during shut-in for a typical shale reservoir Jimsar. The results indicate that the microscopic advancement mechanism of the imbibition front is the competitive adsorption between “interfacial water molecules” at the imbibition front and “adsorbed oil molecules” on the pore wall. The essence of spontaneous imbibition involves the adsorption and aggregation of water molecules onto the hydroxyl groups on the pore wall. The flow characteristics of shale oil suggest that the overall push of the injected water to the oil phase is the main reason for the displacement of adsorbed oil molecules. Thus, shale oil especially the heavy hydrocarbon component in the adsorbed layer tends to slip on the walls. However, the weak slip ability of heavy components on the wall surface is an important reason that restricts the displacement efficiency of shale oil during spontaneous imbibition. The effectiveness of spontaneous imbibition is strongly dependent on the hydrophilicity of the matrix pore's wall. The better hydrophilicity of the matrix pore's wall facilitates higher levels of adsorption and accumulation of water molecules on the pore wall and requires less time for “interfacial water molecules” to compete with adsorbed oil molecules. During the forced imbibition process, the pressure difference acts on both the bulk oil and the boundary adsorption oil, but mainly on the bulk oil, which leads to the occurrence of wetting hysteresis. Meanwhile, shale oil still existing in the pore always maintains a good stratified adsorption structure. Because of the wetting hysteresis phenomenon, as the pressure difference increases, the imbibition effect gradually increases, but the actual capillary pressure gradually decreases and there is a loss in the imbibition velocity relative to the theoretical value. Simultaneously, the decline in hydrophilicity further weakens the synergistic effect of pressure difference because of the more pronounced wetting hysteresis. Thus, selecting an appropriate well pressure enables cost savings and maximizes the utilization of the formation's natural power for EOR.

Dysregulation of the Cyclin-dependent kinase 8 (CDK8) activity has been associated to many diseases including the colorectal and breast cancer. As usual in the CDK family, the activity of CDK8 is controlled by a regulatory protein called cyclin C (CycC). But while human CDK family members are generally activated in two steps that is, the binding of the cyclin to CDK and the phosphorylation of a residue in the CDK activation loop, CDK8 does not require the phosphorylation step to be active. Another peculiarity of CDK8 is its ability to be associated to CycC while adopted an inactive form. These specificities raise the question of the role of CycC in the complex CDK8-CycC, which appears to be more complex than for the other members of CDK family. Through MD simulations and binding free energy calculations, we investigated the effect of CycC on the structure and dynamics of CDK8 on the one hand, and the structural molecular basis of the protein-protein interaction between the two partners on the other hand. We found that CycC has a stabilizing effect on CDK8 and identified specific interaction hotspots within its interaction surface compared to other human CDK/Cyc pairs. Targeting these specific interaction hotspots could be a promising approach in terms of specificity, to effectively disrupt the interaction between CDK8. The simulation of the conformational transition from the inactive to the active form of CDK8 suggests that the residue Glu99 of the CycC may assume the role of the missing phosphorylation step in the activation mechanism of CDK8. In a more general view, these results point the importance of keeping the CycC in computational studies when studying the human CDK8 protein in both the active and the inactive form.

Marburg virus disease (MVD) is a hemorrhagic fever and cause death up to 88% of people and is the same as Ebola virus, It is transmitted through skin contact or mucous membrane in the eyes, nose or mouth with blood or body fluids like urine, saliva sweat, feces and by object contaminated with body fluids. Despite these facts, yet there is no approved vaccine have been developed for the eradication of Marburg virus infections. Therefore, this study described a multi epitope-based peptide vaccine against Marburg virus viral protein 35, using several immunoinformatics tools combined with molecular docking studies. Utilizing Vaxijen 2.0 server, the V35 protein revealed to be antigenic with a score of 0.4316. Prediction of the T-cell and B-cell epitopes was then conducted. RTFDAFLGV epitope was found to be the most promising one with binding affinity to the highest numbers of MHC I alleles, a positive score in the Class I immunogenicity study and non-allergen. These results were further confirmed by the good interaction of RTFDAFLGV to the groove of HLA-A*02:01 with binding energy of -8.1 kcal/mole. Finally, the vaccine was cloned in silico to ensure its validity and efficiency of expression. To ensure its safety and immunogenic profile, in-vitro and in-vivo bioassays are recommended to confirm these findings.

This study employs molecular docking experiments to investigate the binding interactions of Hypericin with key proteins implicated in Alzheimer's disease (AD). Hypericin demonstrated a significant binding energy of -10.1 kcal/mol with ABAD (3-hydroxyacyl-CoA dehydrogenase type II). The analysis revealed multiple binding interactions, including hydrogen bonds with arginine 6, serine 7, and glutamic acid 140, as well as hydrophobic bonds involving leucine 11, aspartic acid 142, and aspartic acid 86. These findings illuminate the intricate molecular interactions between Hypericin and ABAD, suggesting its potential as a lead compound for further therapeutic development in the context of Alzheimer's disease. Additionally, a parallel docking investigation was conducted for Beta-secretase 1 (BACE1), a protein pivotal in the generation of beta-amyloid peptides—a hallmark of Alzheimer's disease. Inhibiting BACE1 activity is considered a promising therapeutic strategy for AD. Computational analyses suggest that Hypericin may serve as a potential inhibitor of BACE1. Molecular Docking results reveal a robust binding affinity between Hypericin and BACE1, supported by a significant binding energy score of -10.3 kcal/mol. Notably, both ABAD and BACE1 exhibit high binding affinity with Hypericin. This theoretical exploration provides an initial understanding of the intricate molecular pathways involved in Alzheimer's disease and proposes Hypericin as a potential therapeutic compound for mitigating its progression.

Investigations are currently in progress to assess the potential of elevated FABP3 levels as biomarkers for assessing cardiac and cerebral injury post-stroke. Ongoing research endeavors are concentrated on elucidating the specific mechanisms by which FABPs, particularly FABP3, contribute to the complex processes involved in ischemic stroke. This study employs molecular docking techniques within a Virtual Screening framework to examine the interaction between various natural substances and the active site of human heart fatty acid-binding protein (PDB Code 4TKH). Utilizing Pyrx and Autodock Vina, the research aims to pinpoint compounds demonstrating robust binding interactions, characterized by high binding energy scores (kcal/mol) and the formation of multiple chemical bonds. The anticipated outcomes have the potential to yield valuable insights into the molecular interactions influencing human heart fatty acid-binding protein, suggesting possible implications for therapeutic interventions using these natural substances.From the docking and predicted toxicity results, Resistomycin has demonstrated superior characteristics compared to Morusin.

This dissertation presents a method for the synthesis of substituted indoles bearing heterocyclic substituents onto the 3- position. The route for the synthesis of the heterocyclic substituents indoles starts from 3-acetyl indole nucleus depend on two parts. One part: Reaction of 3-acetylindole 1 with hydrazide compounds such as phenyl hydrazine, hydrazine hydrate, and thio-semicarbazide, to yield 3-(1-(2-phenylhydrazono) ethyl)-1H-indole 2, 3-(1-hydrazonoethyl)-1H-indole 6, and thiosemicarbazone 10 respectively. 3-(1-Hydrazonoethyl)-1H-indole 6 reacted with thiophene-2-carboxaldeyde, isatin and 3-acetyl indole. In the same way, 3-(1-(2-phenylhydrazono) ethyl)-1H-indole 2 reacted with thioglycollic acid, glycine and benzaldehyde. 3-Acetylindole 1 thiosemicarbazone reacted with acetic anhydride, piperidine, concentration of hydrochloric acid and thiophene-2-carboxaldeyde. Second part. Reaction of 3-acetyl indole 1 with amines compounds such as p-nitroaniline to formed Schiff base 15 which it reacted with thioglycollic acid to give compound 16. 3-Acetyl indole 1 reacted with ethylene diamine to afford bis imine indole to afford compound 17. The reports of this docking study revealed that the new compounds exhibit good antibacterial activity. The synthesized compounds screened in vitro for their antibacterial activity revealed remarkable inhibitory effects against the selected microorganisms. And also an anti-oxidant activity studying for some synthesized compounds. Structures of the newly synthesized compounds examination by spectral data (IR, 1H- NMR and 13C -NMR).

Cirsium japonicum, a traditional herb, exhibits significant anti-inflammatory activity; however, the main components and potential mechanisms of C. japonicum remain unclear. The aim of this study is to investigate the anti-inflammatory mechanism of Cirsium japonicum through network pharmacology and cellular experiments. The effective components and potential targets for anti-inflammatory activity of C. japonicum were identified using traditional Chinese medicine systematic pharmacology database, TCMSP analysis platform, and GeneCards database. The drug-component-target-disease network diagram was constructed using Cytoscape3.8.0 software, while the protein interaction network diagram was created using STRING database and Cytoscape3.8.0 software. Gene ontology (GO) enrichment and KEGG pathway enrichment analysis were carried out using DAVID database. Molecular docking between key targets and active components was constructed with AutoDock software to determine the best binding target. Results revealed that 14 active components of C. japonicum targeted 171 anti-inflammatory proteins. GO function enrichment analysis yielded 173 items, while KEGG pathway enrichment analysis identified 48 signaling pathways related to inflammation regulation. Molecular docking showed that strong affinity between sitosterol, stigmasterol, and other components with key targets such as peroxisome proliferator-activated receptor α recombinant protein (PPARA) and cyclooxygenase-2 (PTGS2). Vanillin, one active ingredient of C. japonicum, inhibited the release of lipopolysaccharide (LPS)-induced inflammatory factors in RAW264.7 cells. These findings suggest that C. japonicum may exert its anti-inflammatory effects by modulating the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (Akt) signal pathway (PI3K-Akt) and apoptin signal pathway, highlighting the multi-component, multi-target, and multi-channel molecular mechanism underlying its anti-inflammatory properties. Finally, the anti-inflammatory effect of vanillin, an effective component in C. japonicum, was verified by cell experiments. This study provides a new understanding of the pharmacological mechanisms of C. japonicum in treatment of inflammatory conditions.

Cervical cancer is a significant global health concern, with human papillomavirus (HPV) infection being a crucial risk factor. Photodynamic therapy (PDT) is an attractive, minimally invasive treatment for HPV-related cervical lesions, which uses photosensitizers and light to selectively de-stroy abnormal cells. We aim to provide an overview of the various sorts of dyes that are utilized in PDT for decreasing the incidence and mortality of cervical cancer. Besides, the article discusses ongoing clinical trials for PDT in low-grade squamous intraepithelial neoplasia (LSIL) and high-grade squamous intraepithelial lesions (HSIL), as well as preclinical approaches for PDT in cervical cancer using various dyes. Moreover, it highlights potential dyes for PDT, examine them in in-silico condition, their pros and cons and also the solutions for enhancing their anticancer com-patibility. We also display that PDT is a promising therapeutic strategy for the diagnosis and treatment of HPV-associated cervical lesions. Moreover, it shows that using different classes of dyes improves the anticancer effects of PDT. Finally, among all dyes which are used in PDT, Fullerene demonstrated high tendency to over expressed receptors in cervical cancer cells and seems to be a proper candidate for be used in PDT more than before, but further research is necessary to assess its long-term efficacy and safety.

We report a detailed investigation of vibrational modes, structure, and dynamics of glutathione (GSH) solutions using ultrasonic relaxation spectroscopy, FT-IR vibrational spectroscopy and electronic absorption measurements. The experimental data were analyzed in view of density functional theory (DFT) and molecular docking calculations. Three distinct Debye-type relaxation processes are resolved in the acoustic spectra, which are assigned to conformational changes between GSH conformers, self-association of GSH, and protonation processes. The standard volume changes for each process were estimated both experimentally and theoretically revealing a close resemblance among them. The higher the effect of the relaxation process in the structure, the greater the induced volume changes. From the temperature dependence of specific acoustic parameters, the thermodynamic characteristics of each process were determined. The experimental FT-IR spectra were compared with the corresponding theoretically predicted vibrational spectra revealing that the GSH dimers and extended conformers dominate the structure of GSH solutions in the high concentration region. The absorption spectra in the ultraviolet region confirmed the gradual aggregation mechanism that takes place in the aqueous GSH solutions. The results of the present study were discussed and analyzed in the framework of the current phenomenological status of the field.

[Co(AMPY)(DAPY)Cl2(H2O)].H2O (1) [Cu(AMPY)(DAPY)Cl2(H2O)].H2O (2) [Zn(AMPY)(DAPY)Cl2(H2O)] (3) were prepared from the ligands; AMPY = 2-amino-4-methylpyrimidine (L1), DAPY = 2,3-diaminopyridine (L2) and CoCl2.6H2O, CuCl2.2H2O and ZnCl2 in water/ethanol solutions and the three products characterized by elemental analysis, ultraviolet-visible spectroscopy (UV–Vis), Fourier-transform infrared spectroscopy (FT-IR), magnetic susceptibility, molar conductivity methods, and TGA analysis. The X-ray powder diffraction of the Co(II), Cu(II), and Zn(II) compounds showed that the geometry of monoclinic and SEM analysis revealed their morphology with a smooth surface. Molecular modeling was performed for all compounds using the density functional method DFT/B3LYP to study the structures and the frontier molecular orbitals (HOMO and LUMO). We have used Gaussian09 software for the calculations. In this study, different complexes were tested against Gram negative and Gram positive bacterial species to give insight into their broad-spectrum effects. The used pathogenic strains were two Gram positive species "Staphylococcus aureus and Micrococcus luteus" and two Gram negative species "Salmonella thyphimurium and Escherichia coli. The antifungal activity was evaluated against a pathogenic reference strain of the yeast Candida albicans. The antimicrobial and antioxidant assay results demonstrate that the tested compounds are effective against Gram positive and negative bacteria. Additionally, the compounds have an antifungal effect against Candida albicans with a maximum inhibitory zone of 2.5cm. The results demonstrated high antioxidant potential for the Zn(II) complex with a DPPH scavenging of 91.5%, however, the Cu(II) complex was low (16.5%). The data of docking with tyrosyl-tRNA synthetase presented that all compounds fit very well in the catalytic pockets of the proteins of the receptor.

As part of valorisation of agricultural waste into bioactive compounds, a series of structurally novel oleanolic acid ((3β-hydroxyolean-12-en-28-oic acid, OA-1)-phtalimidines (isoindolinones) conjugates 18a-v bearing 1,2,3-triazole moieties were designed and synthesized by treating a previously azide 4 prepared from OA-1 isolated from olive pomace (Olea europaea L.) with a wide range of propargylated phtalimidines using the Cu(I)-catalyzed click chemistry approach. OA-1 and its newly prepared analogues 18a-v were screened in vitro for their antibacterial activity against two Gram-positive bacteria, Staphylococcus aureus and Listeria monocytogenes; and two Gram-negative bacteria, Salmonella thyphimurium and Pseudomonas aeruginosa. Attractive results were obtained notably against L. monocytogenes. Compounds 18d, 18g and 18h exhibited the highest antibacterial activity when compared with OA-1 and other compounds in the series against tested pathogenic bacterial strains. Molecular docking study was performed to explore the binding mode of the most active derivatives against the target protein from L. monocytogenes. Results showed the importance of both hydrogen bonding and hydrophobic interactions with the target protein and are in favor to the experimental data.

Glioblastoma multiforme (GBM) is a highly heterogeneous brain tumor with limited treatment options and a poor prognosis. Cancer stem cells (CSCs) have emerged as a critical factor in GBM resistance and management, contributing to tumor growth, heterogeneity, and immunosuppression. The transcription factor FOXM1 has been identified as a key player in the progression, spread, and therapy resistance of various cancers, including GBM. In this study, researchers conducted structure-based in silico screening to identify natural compounds that could target the DNA-binding domain (DBD) of the FOXM1 protein. Through molecular docking analyses, identified Silybin B as a potential inhibitor of FOXM1, exhibiting strong interaction with the protein. MD simulations were performed to validate the binding stability of the FOXM1-Silybin B complex. The study provides valuable insights into the potential of Silybin B as a FOXM1 inhibitor and its ability to induce senescence in GBM stem cells. These findings contribute to the development of structure-based design strategies for FOXM1 inhibitors and innovative therapeutic approaches for the treatment of Glioblastoma.

Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In search for therapeutic alternatives to treat the cancer disease, a se-ries of hybrid pyrazolo[3,4-d]pyrimidin-4(5H)-ones tethered with hydrazide-hydrazones, 5a-h, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide 4 with a series of arylaldehydes in EtOH, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that 5a, 5e, 5g, and 5h were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, 5a, 5e, 5g, and 5h were evalu-ated for their binding interactions with two well-known anticancer targets, namely the epider-mal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of 5a, 5e, 5g, and 5h towards EGFR. CD experi-ments suggested 5a as a stabilizer agent of the G-quadruplex from the KRAS oncogene promot-er. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hy-drazide-hydrazone moiety as a lead skeleton for designing novel anticancer compounds.

Natural and synthetic small molecules from the NCI Developmental Therapeutics Program (DTP) were employed in molecular dynamics-based docking with DNA repair proteins whose RNA-Seq based expression was associated with overall cancer survival (OS) after adjustment for the PCNA metagene. The compounds employed were required to elicit a sensitive response (vs. resistance) in more than half of the cell lines tested for each cancer. Methodological approaches included peptide sequence alignments and homology modeling for 3D protein structure determination, ligand preparation, docking, toxicity and ADME prediction. Docking was performed for unique lists of DNA repair proteins which predict OS for AML, cancers of the breast, lung, colon, and ovaries, GBM, melanoma, and renal papillary cancer. Results indicate hundreds of drug-like and lead-like ligands with best-pose binding energies less than -6 kcal/mol. Ligand solubility for the top 20 drug-like hits approached lower bounds, while lipophilicity was acceptable. Most ligands were also blood-brain barrier permeable with high intestinal absorption rates. While the majority of ligands lacked positive prediction for Herg channel blockage and Ames carcinogenicity, there was considerable variation for predicted fathead minnow, honey bee, and Tetrahymena pyriformis toxicity. The computational results suggest the potential for new targets and mechanisms of repair inhibition and can be directly employed for in vitro and in vivo confirmatory laboratory experiments to identify new targets of therapy for cancer survival.

Chlorotoxin (CTX) is a 36–amino acid peptide with 8 Cys residues that forms four Cys-Cys bonds. It has high affinity for the glioma-specific chloride channel and matrix metalloprotease-2. Structural and binding properties of CTX analogs with various Cys residue substitutions with L-a-aminobutyric acid (Abu) have been previously reported. Using 4.2 ìs molecular dynamics, we compared the conformational and essential space sampling of CTX and analogs [Abu/Ser^2,19]CTX, [Abu/Ser^5,28]CTX, [Abu/Ser^16,33]CTX, [Abu/Ser^20,35]CTX, and [Abu/Ser^{2,5,16,19,20,28,33,35}]CTX. The native and substituted peptides maintained a high degree of a-helix propensity from residues 8 through 21, with the exception of [Ser^5,28]CTX and [Abu^16,33]CTX. In agreement with previous circular dichroism spectropolarimetry results, the C-terminal b-sheet content varied less from residues 25 through 29 and 32 through 36 and was well conserved in all analogs, except: [Abu^16,33]CTX, [Ser^20,35]CTX, [Abu^{2,5,16,19,20,28,33,35}]CTX, and [Ser^{2,5,16,19,20,28,33,35}]CTX. The Cys¹⁶-Cys³³ and Cys²⁰-Cys³⁵ Cys-Cys bonds appear to be required to maintain the ab-motif of CTX. Their selective substitution with Ser^16,33 however, may mitigate the destabilizing effect of Cys¹⁶-Cys³³ substitution by the formation of an inter residue H-bond from OgH of Ser¹⁶ to OgH of Ser³³ bridged by a water molecule. All peptides shared considerable sampled conformational space, which explains the retained receptor binding of the nonnative analogs.

Nuclear export of viral mRNAs, is an essential step in the HIV replication cycle. This role is played by a small regulatory protein of HIV-1 called Rev.The N-terminal region of Rev contains an arginine-rich sequence. The arginine-rich motif (ARM) is located between amino acids 38-50 and forms an alpha-helical secondary structure. Expression of the structural proteins of human immunodeficiency virus type 1 requires the direct interaction of multiple copies of the viral Rev protein with its highly structured RNA target sequence, the Rev Response element (RRE). The major viral proteins are not produced if this transport of RNA is stopped. Therefore, knowledge of Rev structure is essential for understanding of its cooperative binding to the RRE, for understanding the mechanism of HIV infection and for the development of antiviral drugs that interfere with Rev’s essential functions and for acknowledgment of good candidate drugs for treatment of AIDS. To understand how REV interact with RRE element of HIV-RNA and its formation of oligomeric complex it is better to characterize the domain wise structure of REV with regard in function of each domain. Due to lack of structural data on Rev no single compound is reported as inhibitor of REV expect antiviral drugs. Identification of a high-affinity RNA-binding site for the human immunodeficiency virus type 1 Rev Protein is much more important. The ARM is a highly specific sequence which allows for the multimerization of Rev and also binding of REV with RNA. Here we are first time exploring the structural characteristics of REV protein both in free form and in complex with RNA at domain function level especially explore the role of ARM motif in REV HIV-1 protein as RNA binding sites by molecular dynamics (MD) simulation and homology modeling studies. Results indicate that the arginine-rich motif (ARM) is crucial in stability of this complex. The residues ARG38, 39, 41, 43, 44, 48, 50, and ASN40 are most interacting with nucleobases of RRE in Crystal structure of Rev and Rev-response-element RNA complex. Our study plays a major role in elaboration of binding of RNA with REV and pave the way for further investigation for therapeutically agent for HIV.

The aim of the study was to determine the possibility of suppression of the prostaglandin synthesis by new derivatives of N-phenylanthranilic acids; they inhibit the activity of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme using the method of a flexible molecular docking. For the docking studies the crystallographic structural models with high resolution from Protein Data Bank were used: mPGES-1 in the complex with glutathione (pdb code 4AL0). A flexible molecular docking was carried out using the Molecular Operating Environment (MOE) software package. According to the results of the docking studies four scoring functions were calculated (Affinity dG Scoring, Alpha HB Scoring, London dG Scoring, GBVI/WSA dG Scoring). The values of the scoring functions calculated indicate the thermodynamic probability and energy favorability of forming complexes between molecules of the substances under research and the specified receptor, in which arrangement of ligands in the active site of the receptor and residues of amino acids of side chains are of similar geometry and types of binding of the known inhibitors of mPGES-1 determined on the basis of the crystallographic studies.

According to our previous investigation the total methanol extract from Graptopetalum paraguayense E. Walther demonstrates a significant inhibitory effect on HSV-1. To clarify what causes this inhibitory activity on HSV-1, a metabolic profile of the plant was performed. Three main fractions: non-polar substances, polar metabolites and phenolic compounds were obtained and GC-MS analysis was carried out. Since it is well known that phenolic compounds show a significant anti-herpes effect and that viral DNA polymerase (DNApol) appears to play a key role in HSV virus replication, we present a docking and quantum-chemical analysis of the binding of these compounds to viral DNApol amino acids. Fourteen different phenolic acids found by GS/MS analyses, were used in molecular docking simulations. According to the interaction energies of all fourteen ligands in the DNApol pockets based on docking results, DFT calculations were performed on the five optimally interacting with the receptor acids. It was found that hydroxybenzoic acids from phenolic fraction of Graptopetalum paraguayense E. Walther show a good binding affinity to the amino acids from the active site of the HSV DNApol, but significantly lower than that of acyclovir. The mode of action on virus replication of acyclovir (by DNApol) is different from that of the plant phenolic acids one, probably.

Aims: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. This paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 co-crystallized with COVID-19 spike protein. Methods: First, the starting point was ACE2 inhibitors and their structure-activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. In parallel, at all stages, authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 co-crystallized with COVID-19 spike protein. Results: Carnosine emerged as the best known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the co-crystallized protein structure, carnosine bind with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Conclusion: Carnosine has promising inhibitory interactions with host ACE2 co-crystallized with COVID-19 spike protein and hence could offer potential mitigating effect against current COVID-19 pandemic.

The Novel Coronavirus (COVID-19) is a positive-sense single-stranded RNA ((+)ssRNA) virus. The COVID-19 Main Proteases play very important role in the propagation of the Novel Coronavirus (COVID-19). It has already killed more than 8000 people around the world and thousands of people are getting infected every day. Therefore, it is very important to identify a potential inhibitor against COVID-19 Main Proteases to inhibit the propagation of the Novel Coronavirus (COVID-19). We have applied a drug repurposing approach of computational methodology, depending on the synergy of molecular docking and virtual screening techniques, aimed to identify possible potent inhibitors against Novel Coronavirus (COVID-19) from FDA approved antiviral compounds and from the library of active phytochemicals. On the basis of recently resolved COVID-19 Main Protease crystal structure (PDB:6LU7), the library of 100 FDA approved antiviral compounds and 1000 active components of Indian Medicinal Plants extracted for screening against COVID-19 Main Protease. The compounds were further screened using Pyrex virtual screening tool and then best inhibitors, top 19 compounds optimally docked to the COVID-19 Main Protease structure to understand the participation of specific amino acids with inhibitors at active sites. Total 19 best compounds were identified after screening based on their highest binding affinity with respect to the other screened compounds. Out of 19, 6 best compounds were further screened based on their binding affinity and best ADME properties. Nelfinavir exhibited highest binding energy -8.4 kcal/mol and strong stability with the TRP207, ILE281, LEU282, PHE3, PHE291, GLN127, ARG4, GLY283, GLU288, LYS5, LYS137, TYR126, GLY138, TYR126, SER139 and VAL135 amino acid residues of COVID-19 Main Protease participating in the interaction at the binding pocket. In addition to Nelfinavir (-8.4), Rhein (-8.1), Withanolide D (-7.8), Withaferin A (-7.7), Enoxacin (-7.4), and Aloe-emodin (-7.4) also showed good binding affinity and best ADME properties. Our findings suggest that these compounds can be used as potential inhibitors against COVID-19 Main Protease, which could be helpful in inhibiting the propagation of the Novel Coronavirus (COVID-19). Moreover, further in vitro and in vivo validation of these findings would be very helpful to bring these inhibitors to next level study.

In the course of SARS-CoV-2 infection, the 3CL or nsp5 protease plays a pivotal role as the most important viral protease required for the maturation of viral proteins during host infection. Herein, we simulated for 500 ns 3CLproWT, 3CLproH41A, , 3CLproBeta, and 3CLproOmicron, in complex with the substrates nsp 4|5 and nsp 5|6. Our results show that mutations in the 3CLpro present in the SARS-CoV-2 variant of concerns (VOCs) did not lead to significant conformational changes or changes in substrate binding affinities. However, significantly high cleavage rates for the boundary between nsp4 and nsp5 were obtained for 3CLproBeta and 3CLproOmicron and may play a key role in the viral replication and virus fitness gain. Our molecular dynamics data suggest that the cleavage rate of nsp4|5 may be related to the increased amount of viral load observed for these VOCs, releasing more nsp4 than other non-structural proteins. Based on our hydrogen bonding analyses, we also discovered that Gly143 and Glu166 are key residues in substrate recognition, suggesting that these residues may be incorporated as pharmacophoric centers for Beta and Omicron variants in drug design. Our results suggest that Gly143 and Glu166 are essential residues to interact with Gln6 of the different substrates and, therefore, are potential broad-spectrum pharmacophoric centers of SARS-CoV-2 3CLpro.

Structurally related 7-acetyl-2-aryl-5-bromoindoles 2a–d and the 7-acetamido-2-aryl-5-bromoindoles 4a–d as well as their corresponding 3-trifluoroacetyl–substituted derivatives 5a–d and 5e–h were evaluated for potential antigrowth effect in vitro against the human lung cancer (A549) and cervical cancer (HeLa) cells. All of the 3-trifluoroacetyl–substituted 7-acetamido-2-aryl-5-bromoindoles 5e–h were found to be more active against both cell lines when compared to the chemotherapeutic drug, Melphalan. The most active compound 5g induced apoptosis in a caspase dependent manner for both cell lines. Compounds 5e–h were found to significantly inhibit tubulin polymerization. Molecular docking of 5g into the colchicine-binding site suggests that the compounds bind to tubulin by different type of interactions including pi-alkyl, amide-pi stacked and alkyl interactions as well as hydrogen bonding with the protein residues to elicit anticancer activity.

Electrostatic interactions have a determining role in conformational and dynamic behavior of polyelectrolyte molecules [1]. In this study, anionic polyelectrolyte molecules, poly(glutamic acid) (PGA) and poly(aspartic acid) (PASA), in water solution with the most commonly used K+ or Na+ counterions were investigated using atomistic molecular dynamics (MD) simulations. Seven common force fields, AMBER99SB-ILDN, AMBER14SB, AMBER-FB15, CHARMM22*, CHARMM27, CHARMM36m and OPLS-AA/L, both with their native parameters and with the non-bonded fix (NBFIX) and electronic continuum corrections (ECC) to were studied. These corrections have bene introduced to correct for the problem of overbinding of ions to the charged groups of polyelectrolytes. Physical properties, such as molecular sizes, local structure and dynamics, were studied using two types of common counterions, potassium and sodium. The results show that in some cases, the macroion size and dynamics depend strongly on the models (parameters) for the counterions due to strong overbinding of ions and charged side chain groups. The local structures and dynamics are more sensitive on dihedral angle parameterization resulting in a preference for defined monomer conformations amd the type of correction used.

ND1 subunit possesses the majority of the inhibitor binding domain of the human MRC-I. This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, some metabolites from Annona muricata called acetogenins have important biological activities such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine MRC-I by bis-THF acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human MRC-I. In this work, we evaluate the molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, QM optimizations, MD simulations and MM/PBSA analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known MRC-I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger BFE compared to the rotenone complex. Detailed analysis of the BFE shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of MRC-I.

2-(Adamantan-1-yl)-2H-isoindole-1-carbonitrile (1) has been identified as a neurobiological fluorescent ligand that may be used to develop receptor and enzyme binding affinity assays. Compound 1 was synthesised using an optimised microwave irradiation reaction and crystallised from ethanol. Crystallization occurred in the orthorhombic space group P212121 with unit cell parameters: a = 6.4487(12) Å, b = 13.648(3) Å, c = 16.571(3) Å, V = 1458(5) Å3, Z = 4. Density functional theory (DFT) (B3LYP/6-311++G (d,p)) calculations of 1 were carried out. Results showed that the optimised geometry is similar to the crystal structure parameters with a root-mean-squared deviation of 0.143 Å. Frontier molecular orbital energies and net atomic charges are discussed with a focus on potential biological interactions. Docking experiments within the active site of the neuronal nitric oxide synthase (nNOS) protein crystal structure were carried out and analysed. Important binding interactions between the DFT optimised structure and amino acids within the nNOS active site were identified that explain the strong NOS binding affinity reported. Fluorescent properties of 1 were studied using aprotic solvents of different polarities. Compound 1 showed the highest fluorescence intensity in polar solvents with excitation and emission values of 336 nm and 380 nm, respectively.

A series of novel substituted isoxazolidine derivatives was synthesized through 1,3-dipolar cycloaddition reactions of α-aryl-N-methyl nitrones with various ethylene moieties, resulting in the formation of isoxazolidine derivatives. The structures of the synthesized compounds were characterized using spectroscopic methods. The [3+2] cycloaddition (32CA) reactions of α-aryl-N-methyl nitrones with diverse ethylene substituents were computed employing Density Functional Theory (DFT) at the B3LYP/6–31G(d) level, upgrading bond parameters. An investigation of the electron localization function (ELF) unveiled the zwitterionic nature of α-aryl-N-methyl nitrones, devoid of pseudoradical or carbenoid centers. Utilization of CDFT indices enabled the prediction of global electronic flux from the strongly nucleophilic α-aryl-N-methyl nitrones to the varied electrophilic ethylene functionalities. Molecular docking and molecular dynamics simulations were conducted on the isoxazolidine derivatives against the EGFR receptor (PDB: 4ZAU). In silico assessment of the synthesized isoxazolidines involved molecular docking, wherein the compound with the highest docking score was subjected to molecular dynamics simulations. Compound 11a, out of the thirty isoxazolidine derivatives, displayed the most substantial binding energy, yielding a g score of -6.57 kcal/mol. These observations highlighted the functional role of amide NH2 and NO2 in the binding process with the target protein, influencing its activity. Furthermore, prediction of ADME drug-likeness properties was performed to identify a suitable candidate.

In its prefusion state, the SARS-CoV-2 Spike protein (similarly to other class I viral fusion proteins) is metastable, which is considered to be an important feature for optimizing or regulating their functions. After the binding process of its S1 subunit (S1) with the ACE2, the Spike protein (S) suffers a dramatic conformational change where S1 splits from the S2 subunit, which then penetrates the membrane of the host cell, promoting the fusion of the viral and cell membranes. This results in the infection of the host cell. In a previous work, we showed -using large scale molecular dynamics simulations- that the application of external electric fields (EF) induces drastic changes and damage in the receptor-binding domain (RBD) of the wild type Spike protein, as well of the Alpha, Beta and Gamma variants, leaving a structure which cannot be recognized any more by ACE2. In this work, we first extend the study to the Delta and Omicron variants and confirm the high sensitivity and extreme vulnerability of S to moderate EF (as weak as 104 V m-1), but, more importantly, we also show that, in contrast, the postfusion state of the spike protein does not suffer structural damage even if electric field intensities four orders of magnitude higher are applied. These results provide a solid scientific basis to confirm the prefusion state metastability roots of the SARS-CoV-2 Spike protein susceptibility to be damaged by EF. After the virus docks to the ACE2 receptor, the stable and robust postfusion conformation develops, which exhibits a similar resistance to EF (damage threshold higher than 108 V m-1) like most globular proteins.

The current study describes the preparation of chitosan nanoparticles (CNPs) using hydroxychloroquine (HCQ), widely used in traditional medicine due to its diverse phar-macological and medicinal uses. This work aims to combine the HCQ drug with CS NPs to generate a novel nanocomposite with improved characteristics and bioavailability. HCQ@CS NPs is roughly shaped like roadways and has a smooth surface with an average size of 159.3±7.1 nm, a PdI of 0.224±0.101, and a zeta potential of +46.6±0.8 mV. To aid in the development of pharmaceutical systems for use in cancer therapy, the binding mech-anism and affinity of the interaction between HCQ and HCQ@CS NPs and BSA were ex-amined using stopped-flow, other spectroscopic approaches, supplemented by molecular docking analysis. HCQ and HCQ@CS NPs binding with BSA is driven by a ground-state complex formation that may be accompanied by a non-radiative energy transfer process, and binding constants indicated that HCQ@CS NPs-BSA was more stable than HCQ-BSA. The stopped-flow analysis demonstrated that, in addition to increasing BSA affinity, the nano formulation HCQ@CS NPS changes the binding process and may open up new routes for interaction. Docking experiments verified the development of the HCQ-BSA complex, with HCQ binding to the site I on the BSA structure, primarily with the amino acids Thr 578, Gln 579, Gln 525, Tyr 400, and Asn 404. Furthermore, the nano-formulation HCQ@CS NPS not only increased cytotoxicity against the A549 lung cancer cell line (IC50 = 28.57±1.72 g/ml) compared to HCQ (102.21±0.67) g/ml), but also exhibited higher anti-bacterial activity against both Gram-positive and Gram-negative bacteria when compared to HCQ and chloramphenicol which in agreement with the binding constants. The nano formulation developed in this study may offer a viable therapy option for A549 lung cancer.

This study investigates the use of artificial intelligence (AI) and ethnobotanical knowledge to identify natural compounds with potent antiviral activity against HPV-16. Through molecular docking simulations, we evaluated the binding affinities of various essential oil components, in-cluding Apigenin, against the key antigenic determinants of HPV-16 (E6, E7 oncoproteins, and L1 major capsid protein). Apigenin exhibited strong binding affinities, particularly to E6 Oncopro-tein. To further enhance these findings, we employed an AI-driven reverse engineering approach to predict a natural compound with superior efficacy. The AI identified Luteolin, a flavonoid with additional hydroxyl groups, as a promising candidate. Comparative docking studies demon-strated that Luteolin possesses significantly stronger binding affinities to all three HPV-16 targets, surpassing the efficacy of Apigenin. This work highlights the potential of AI in accelerating the discovery and optimization of natural antiviral agents, providing a powerful tool for pharmaco-logical and ethnopharmacological screenings. Our findings suggest that AI-guided identification of natural compounds can lead to the development of more effective antiviral therapies, warranting further experimental validation and potential synthesis in laboratory settings.

The formula Chong-Lou-Yao-Fang (CLYF) is an herbal medicinal formulation developed by the indigenous Naxi people for treating liver cancer. This study is to reveal the biological activity, potential targets, and molecular mechanisms of CLYF for cancer treatment through network pharmacology, molecular docking and in vitro experiments. 35 key compounds were screened from 176 active ingredients in CLYF, which played a vital role in the treatment of cancer, 20 core targets were filtered through protein–protein interaction (PPI) network analysis. The enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) indicated that PI3K-Akt, MAPK, hepatitis B, hepatitis C might be effective in liver cancer treatment. Mo-lecular docking revealed stable binding between EGFR, TP53, and AKT1 with active ingredients. Experiments with cell cultures confirmed that CLYF-A suppressed the proliferation of HepG2 cells, which is consistent with the network pharmacology approach undertaken and the predictions of molecular docking. CLYF-A also induced significant apoptosis and cell cycle arrest in HepG2 cells, which was associated with the loss of mitochondrial membrane potential. This study explored the biological activity, potential targets, and molecular mechanisms of CLYF for cancer treatment. Our results may provide a scientific basis for the clinical use of CLYF for cancer treatment and have important implications for developing pharmaceutical preparations, which also need more phar-macological experiments.

Periodontitis is a disease that originates from gingival tissue, and if left untreated, can cause inflammation to spread to deeper tissues, altering bone homeostasis, and even leading to tooth loss. When the bacteria in plaque reach sufficient numbers, the immune system responds by activating immune cells that will produce cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). These immune signaling molecules will coordinate the inflammatory responses. IL-1 binds to the IL-1 receptor (IL-1R) on the surface of target cells, initiating an inflammatory response by activating intracellular signalling pathways. Inhibition of IL-1R can prevent the interaction of IL-1 with this receptor, thereby halting the activation of the inflammatory pathway. By substituting this connection with active anti-inflammatory substances, it is possible to prevent the contact between IL-1 and IL-1R. The licorice plant, Glycyrrhiza glabra, includes eight types of flavonoids with significant anti-inflammatory potential, namely isoliquiritigenin, glyzaglabrin, prunetin, shinpterocarpin, licochalcone A, glabridin, glisoflavone, and isoangustone A. This study aims to assess the potential of such flavonoids as candidates for periodontitis treatment through molecular docking, using AutoDock Tools v.1.5.6. All tested compounds showed highly stable bonds to IL-1R, with a binding affinity values below -7 kcal/mol. Van der Waals forces, hydrogen bonds, and hydrophobic bonds all contribute to the stability of these interactions. Among the eight tested compounds, glisoflavone, which has a Ki value of 90.89 nM and a ΔG value of -9.61 kcal/mol, has the highest binding stability to IL-1R.

New Schiff base ofN'-((E)-3,3-diphenyl-2,3-dihydro-1H-inden-1-ylidene)-2-((Z)-2-oxoindolin-3-ylidene)hydrazine-1-carbothiohydrazide (HL) and its Co(II),Ni(II), Fe(III), Cu(II), Cd(II), Zn(II) and Mn(II) complexes were created, isolated, and characterized by analytical analysis in good yields of 60 to 90%, UV–Vis, magnetic measurements, molar conductivity, and FT-IR. Additionally, mass spectrometry was used to examine the new ligand complexes' structural characteristics.1H NMR spectroscopy and elemental analysis. Depending on the electronic spectra and magnetic susceptibility measurements, these complexes are predicted to have octahedral molecular geometry. As an example, the quantum chemical properties, bond lengths, and bond angles were discussed. The structural formula for the examined ligand was improved using the Gaussian09 tool. The DFT/B3LYP method was used to calculate the energy gaps and other crucial theoretical features. The prepared hydrazine ligand complexes Co (II), Ni (II), Fe (III), Cu (II), Cd (II), Zn (II) and Mn (II) complexes were evaluated for its antimicrobial properties. As antimicrobial agents, it was found that the organic ligand was less biologically active than the targeted complexes. Gram positive bacteria (3ty7-Staphylococcus), Gram negative bacteria (3t88-Escherichia coli), and fungi (5k04-Candida albicans) all have crystal structures that interact well with the chemicals in the title, according to molecular docking.

The development of saltiness enhancement peptides is important in reducing salt intake and promoting dietary health. Our study aimed to analyze and identify straw mushroom enzymatic peptides with salty taste enhancing effects. The taste-related peptides within the straw mush-room extract were isolated via ultrafiltration and identified using UPLC-Q-TOF-MS/MS. Sub-sequent, E-tongue and sensory analyses unveiled that the ultrafiltration fraction (500-2000 Da) of straw mushroom peptides exhibited a saltiness enhancement effect. The UPLC-Q-TOF-MS/MS analysis identified 220 peptides within the ultrafiltration fractions (500-2000 Da), which were then assessed for their interaction with the T1R1/T1R3 receptor. The investigation underscored the significant involvement of Asp223, Gln243, Leu232, Asp251, and Pro254 in the binding of peptides from triple enzymatically hydrolyzed straw mushrooms to T1R1/T1R3. Based on the binding energy and active site analysis, three peptides were selected for synthesis: DFNALPFK (-9.2 kcal/mol), YNEDNGIVK (-8.8 kcal/mol), and VPGGQEIKDR (-8.9 kcal/mol). Notably, 3.2 mmol of VPGGQEIKDR enhanced a 0.05% NaCl solution to the saltiness level of a 0.15% NaCl solution. Also, 0.8 mmol of YNEDNGIVK elevated a 0.05% NaCl solution to the saltiness of a 0.1% NaCl solution.

This study presents a detailed comparative analysis of Molecular Docking data, focusing on the binding interactions of conventional ligands and natural compounds, Apigenin and Luteolin, with TP-53, pRb, and APOBEC. Utilizing advanced bioinformatics techniques, coupled with Ar-tificial Intelligence software and High-Performance Computing (HPC), we measured and con-trasted the binding energies of these interactions. Additionally, we investigated protein-protein interactions between HPV-16 oncoprotein E6 and tumor suppressors TP-53 and pRb. Our findings demonstrate that the natural compounds Apigenin and Luteolin exhibit significantly higher binding affinities to TP-53, pRb, and APOBEC compared to conventional pharmacological ligands. The binding energies for Apigenin and Luteolin were approximately -6.9 kcal/mol and -6.6 kcal/mol, respectively, indicating their strong potential as therapeutic agents in inhibiting the oncogenic functions of HPV-16. In contrast, conventional ligands showed lower binding affinities, with energies around -4.5 to -5.5 kcal/mol. The study further revealed that the protein-protein interactions between E6 and TP-53, and E6 and pRb, exhibited considerably higher binding en-ergies, approximately -976.7 kcal/mol, due to the multiple interaction sites and the complex nature of protein interfaces. A conversion formula was developed to translate these high-energy inter-actions to a comparable scale for non-protein-protein interactions, highlighting the superior binding potential of natural compounds, which, through the same conversion formula, was shown to be higher than that of interaction between E6 with TP-53 and E6 with pRb. These results underscore the therapeutic promise of Apigenin and Luteolin in preventing HPV-16-related on-cogenesis. By demonstrating their higher binding affinities to crucial tumor suppressors, this study supports the development of natural compound-based therapies. The findings also em-phasize the necessity for further experimental validation to explore these compounds' efficacy in clinical settings. This comprehensive analysis provides a robust framework for understanding the comparative binding interactions and lays the groundwork for innovative therapeutic strategies against HPV-16.

New [1,2]dithiolo[3,4-b]pyridine-5-carboxamides were synthesized through the reaction of dithiomalondianilide (N,N'-diphenyldithiomalondiamide) with 3-aryl-2-cyanoacrylamides or by a three-component reaction involving aromatic aldehydes, cyanoacetamide and dithiomalon- dianilide in the presence of morpholine. The structure of 6-amino-4-(2,4-dichlorophenyl)- 7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamide was con-firmed using X-ray crystallography. To understand the reaction mechanism in detail, density functional theory (DFT) calculations were performed with a Grimme B97-3c composite computa-tional scheme. The results revealed that the rate limiting step is a cyclization process leading to the closure of 1,4-dihydropyridine ring with an activation barrier of 28.8 kcal/mol. Some of dithiolo[3,4-b]pyridines exhibited moderate herbicide safening effects against 2,4-D . Additional-ly, ADMET parameters were calculated and molecular docking studies were performed to identify potential protein targets.

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this work, we combined atomistic simulations and conformational dynamics analysis with the ensemble-based mutational profiling of binding interactions for a diverse panel of SARS-CoV-2 spike complexes with nanobodies. Using this computational toolkit, we identified dynamic signatures and binding affinity fingerprints for the SARS-CoV-2 spike protein complexes with nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E+U, a biparatopic nanobody VHH VE, and a combination of CC12.3 antibody and VHH V/W nanobodies. Through ensemble-based deep mutational profiling of stability and binding affinities, we identify critical hotspots and characterize molecular mechanisms of SARS-CoV-2 spike protein binding with single ultra-potent nanobodies, nanobody cocktails and biparatopic nanobodies. By quantifying dynamic and energetic determinants of the SARS-CoV-2 S binding with nanobodies, we also examine the effects of circulating variants and escaping mutations. We found that mutational escape mechanisms may be controlled through structurally and energetically adaptable binding hotspots located in the host receptor-accessible binding epitope that are dynamically coupled to the stability centers in the distant epitope targeted by VHH U/V/W nanobodies. The results of this study suggested a mechanism in which through cooperative dynamic changes, nanobody combinations and biparatopic nanobody can modulate the global protein response and induce the increased resilience to common escape mutants.

Urinary tract infections (UTIs) affect nearly 50% of women in their lifetime. Uropathogenic Escherichia coli (UPEC) expresses F9/Fml pili tipped with protein FmlH that specifically bind to terminal galactoside and galactosaminoside units in glycoproteins in kidney and bladder cells and colonize host tissues. Traditional UTI treatment using excessive antibiotics has led to the rise of various UPEC antibiotic-resistant strains. An alternative therapeutic approach prevents the initial bacterial attachment on the host cells using competitive FmlH-binding inhibitors. In this study, we have used computer-aided drug design techniques to identify novel glycomimetics that are predicted to bind strongly to UPEC FmlH and inhibit binding to host glycoproteins. We have performed in-silico receptor-based and ligand-based scaffold hopping, and molecular docking to predict novel FmlH-binding glycomimetics with high chemical synthesizability. We have replaced the two major scaffolds of the most potent known FmlH-binding ligand to obtain novel compounds. Additionally, we have applied global machine-learning models to predict ADMET properties of the molecules. Compounds with calculated low ADMET risks were subjected to molecular dynamics simulations and detailed investigation of the FmlH–glycomimetic interactions was performed. We have prepared and supplied a library of 58 novel glycomimetics that can be subjected to further biological activity studies.

Mink astrovirus infection remains a poorly understood disease entity, and the aetiological agent itself causes disease with a heterogeneous course, including gastrointestinal and neurological symptoms. This paper presents cases of astrovirus infection in mink from continental Europe. RNA was isolated from the brains and intestines of animals showing symptoms typical of shaking mink syndrome (n = 6). RT-PCR was used to detect astrovirus genetic material, and the reaction products were separated on a 1% agarose gel. The specificity of the reaction was confirmed by sequencing all samples. The presence of astrovirus RNA was detected in each of the samples tested. Sequencing and bioinformatic analysis indicated the presence of the same variant of the virus in all samples. Comparison of the variant with the sequences available in bioinformatics databases confirmed that the Polish isolates form a separate clade, closely related to Danish isolates. The similarity of the Polish variant to those isolated in other countries ranged from 2.4% (in relation to Danish isolates) to 7.1% (in relation to Canadian isolates). Phylogenetic relationships between variants appear to be associated with the geographic distances between them. To our knowledge, this work describes the first results on the molecular epidemiology of MAstV in continental Europe. The detection of MAstV in Central Europe indicates the need for further research to broaden our understanding of the molecular epidemiology of MAstV in Europe.

Herein, we are proposing two chalcone molecules, (E)-1-(4-methoxyphenyl)-3-(p-tolyl) prop-2-en-1-one and (E)-3-(4-hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl) prop-2-en-1-one, based on the anticancer bioactive molecule Xanthohumol, which are suitable for further in vitro and in vivo studies. Their ability to create stable complexes with the antiapoptotic X-linked IAP (XIAP) protein makes them promising anticancer agents. The calculations were based on ligand-based and structure-based virtual screening combined for the pharmacophore built. Additionally, the structures passed Lipinski's rule for drug use, and their reactivity was confirmed using density functional theory studies. The candidates were chosen between 10639400 compounds, and the docking protocols were evaluated using molecular dynamics simulations.

The inhibition of kynurenine aminotransferase II (KATII) is a target for treating several diseases with an excess of kynurenic acid (KYNA). KATII inhibitors exist, but they have adverse side effects, given their irreversible inhibition mechanism. This study aimed to discover potent and safe inhibitors of KATII by using computational and in vitro methods. We identified herbacetin and (-)-Epicatechin as reversible KATII inhibitors from a small library of natural compounds, whose Glide docking scores (-8.66 kcal mol-1 and-8.16 kcal mol-1, respectively) and MM/GBSA binding energies (-50.30 kcal mol-1 and -51.35 kcal mol-1, respectively), which are higher scores than the standard inhibitor, PF-04859989 (-7.12 kcal mol-1 and -38.41 kcal mol-1, respectively). The ADMET analysis showed that herbacetin and (-)-Epicatechin have suitable pharmacokinetic parameters, are moderately bioavailable, and have a safe toxicity profile. Their KATII inhibitory activity is in the range of IC50 values of 5.98± 0.18 µM and 8.76 ± 0.76 µM, respectively. Furthermore, the MTT assay for cell toxicity showed that the two compounds do not alter HepG2 cell viability at their required concentration for KATII inhibition. These results show that herbacetin and(-)-Epicatechin are suitable for KATII inhibition and appropriate candidates for further development of KATII inhibitors.

Cellular aging is considered as one of the main factors leading to female infertility. The process called “inflammaging”, which was proposed by C. Franceschi in 2014 is characterized by chronic asymptomatic inflammation state resulting to whole body aging and age-associated diseases. In this work the inflammaging model was developed; markers expression associated with SASP (senescence associated secretory phenotype) and cell aging were verified in endometrial cells; the correlation analysis with the known inflammaging markers was done; as well as the age dynamic of markers expression in the groups of young reproductive age and late reproductive age was evaluated. For the first time, the comparative study of the expression of the key signalling molecules involved in the mechanisms of the aging was carried out: IL-6, IL-8, IL-1a, MMP3, SIRT1,6, TERF-1, CALR in endometrial cells in the age aspect and under the influence of the genotoxic stress. The SASP phenotype characterizing the phenomenon of inflammaging can be significantly expanded by the including of the studied molecules - SIRT-1, SIRT-6, TERF, CALR, that we demonstrated for the first time. These signalling molecules may be new therapeutic targets for the age-associated female reproductive system diseases treatment.

Leishmaniasis is a group of neglected infectious, non-contagious diseases caused by parasites of the Leishmania genus which affects millions of people worldwide. The drugs available for its treatment, especially in cases of visceral leishmaniasis, are old, outdated, have serious side effects and in many cases are ineffective due to the emergence of resistant strains. In this context, the search for new candidates for more effective and safer drugs which can become new therapeutic alternatives is a constant need. In this work, 10 new chalcones were synthesized in high yields through Claisen-Schmidt condensation and were evaluated in vitro against Leishmania infantum promastigotes and amastigotes. CP04 and CP06 compounds were the most promising, respectively showing IC50 values = 13.64 ± 0.25 and 11.19 ± 0.22 against promastigotes, and IC50 = 18.92 ± 0.05 and 22.42 ± 0.05 against amastigotes. The compounds did not show cytotoxicity in erythrocytes, showing selectivity indexes greater than 74 and 90. Molecular docking studies carried out under the sterol 14-alpha demethylase (CYP-51) (PDB: 3L4D) and trypanothione reductase (PDB: 5EBK) enzymes from L. infantum evidenced the great affinity of the CP04 molecule for these targets, showing Moldock score values of -94.0758 and -50.5692 KJ/mol-1, with these values being much lower than the co-crystallized ligand energies. Molecular dynamics simulations demonstrated great stability of CP04 in its targets, thus indicating a real interaction possibility. Our findings confirm the potential that chalcones have as candidates for anti-leishmania drugs, and suggest that the CP04 compound may become a promising drug candidate to design and develop novel chalcone-based analogs for leishmaniosis therapy.

Oleanolic acid (OA) being the ubiquitous compound in the plant kingdom is studied for both the neuroprotective and neurotoxic properties. The mechanism of acetylcholinesterase (AChE) inhibitory potential of OA is investigated using the molecular dynamic simulations (MD) and docking as well as membrane-like and in vitro tests. There are also applied SH-SY5Y human neuroblastoma cells as well as in vivo on the zebrafish tests. The inhibitory potential towards the AChE enzyme is examined using the TLC-bioautography assay (the IC50 value is 9.22 μM). The CH- interactions between the central fragment of the ligand molecule and the aromatic cluster created by the His440, Phe288, Phe290, Phe330, Phe331, Tyr121, Tyr334, Trp84 and Trp279 side chains are observed. The in vitro tests carried out on the SH-SY5Y cells indicates that the viability rate is reduced to 71.5%, 61%, and 43% at the concentrations of 100 µg/mL, 300 µg/mL, and 1000 µg/mL, respectively after 48 hours of incubation whereas cytotoxicity against the tested cell line with the IC50 value is 714.32 ± 32.40 µg/mL. The in vivo tests on the zebrafish prove that there is no difference between the control and experimental groups as regards the mortality rate and morphology (P>0.05).

Molecular classifications of colorectal cancer (CRC) are benefitting cancer research by providing insights into subtype-specific disease prognosis and better therapeutic intervention. So far different conventional DNA markers such as microsatellite instability (MSI), CpG island methylator phenotype (CIMP), chromosomal instability (CIN), and BRAF and KRAS mutations have been used to classify CRC patients but have not shown promising prognostic values. Here, for the first time, we show classification of CRC tumors from Saudi Arabian patients based on gene expression profile (GEP). An existing method of CRC subtyping has been applied to the GEP of tumors from Saudi CRC patients. Survival analysis was carried out on predicted CRC subtypes. In-silico functional analyses were conducted on the gene signature used for subtype prediction. The predicted subtypes showed distinct but statistically insignificant overall survival distribution (log-rank test, p = 0.069). Comparison of predicted subtypes in Saudi CRC patients with that of the French one showed significant dissimilarity in the two populations (Chi-square test, p = 0.0091). Functional analyses of the gene signature used for subtyping suggest their association with “cancer” and “gastrointestinal diseases”. Most of the signature genes were found differentially expressed in CRC tumors compared to adjacent normal tissues. Such a classification framework might help improve the treatment of colorectal cancer patients.

Amorphous solid dispersions are considered a promising formulation strategy for the oral delivery of poorly soluble drugs. The limiting factor for the applicability of this approach is the physical (in)stability of the amorphous phase in solid samples. Minimizing the risk of reduced shelf life for a new drug by establishing a suitable excipient/polymer-type from first principles would be desirable to accelerate formulation development. Here we perform Molecular Dynamics simulations to determine properties of blends of eight different polymer-small molecule drug combinations for which stability data is available from a consistent set of literature data. We calculate thermodynamic factors (mixing energies) as well as mobilities (diffusion rates and roto-vibrational fluctuations). We find that either of the two factors, mobility and energetics, can determine the relative stability of the amorphous form for a given drug. Which factor is rate limiting depends on physico-chemical properties of the drug and the excipients/polymers. The methods outlined here can be readily employed for an in-silico pre-screening of different excipients for a given drug to establish a qualitative ranking of the expected relative stabilities, thereby accelerating and streamlining formulation development.

This study employs a comprehensive computational approach to identify and evaluate potential inhibitors of gamma D crystallin (CRYGD), a key protein implicated in cataract formation. A library of compounds, including natural products and FDA-approved drugs, was screened using molecular docking simulations and binding energy calculations. The top-scoring compounds were further assessed for drug-likeness properties and potential toxicity. Molecular dynamics simulations were conducted on the most promising candidates to investigate their interactions with CRYGD at the atomic level. The study identified CNP0185903, CID 3741, and CNP0151361 as the most promising compounds, with CNP0151361 demonstrating the most favorable combination of binding affinity, structural stabilization, and conformational modulation of CRYGD. These findings provide a foundation for the development of novel pharmacological interventions for cataract treatment, potentially offering alternatives or complements to current surgical approaches.

Background: Selectively targeting dopamine receptors has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases evolving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elucidated. Methods: Homology modeling and molecular dynamics were applied to construct robust conformational models of all dopamine receptor subtypes (D1-like and D2-like receptors). Fifteen structurally diverse ligands were docked to these models. Contacts at the binding pocket were fully described in order to reveal new structural findings responsible for DR sub-type specificity. Results: We showed that the number of conformations for a receptor:ligand complex was associated to unspecific interactions > 2.5 Å and hydrophobic contacts, while the decoys binding energy was influenced by specific electrostatic interactions. Known residues such as 3.32Asp, the serine microdomain and the aromatic microdomain were found interacting in a variety of modes (HB, SB, π-stacking). Purposed TM2-TM3-TM7 microdomain was found to form a hydrophobic network involving Orthosteric Binding Pocket (OBP) and Secondary Binding Pocket (SBP). T-stacking interactions revealed as especially relevant for some large ligands such as apomorphine, risperidone or aripiprazole. Conclusions: This in silico approach was successful in showing known receptor-ligand interactions as well as in determining unique combinations of interactions, key for the design of more specific ligands.