Liver fibrosis, a consequence of chronic liver damage or inflammation, is characterized by the excessive buildup of extracellular matrix components. This progressive condition significantly raises the risk of severe liver diseases like cirrhosis and hepatocellular carcinoma. The lack of approved therapeutics underscores the urgent need for novel anti-fibrotic drugs. Hepatic stellate cells (HSCs), key players in fibrogenesis, are promising targets for drug discovery. This study investigated the anti-fibrotic potential of Citrus hystrix DC. (KL) and its bioactive compound, β-citronellol (β-CIT), in a human HSC cell line (LX-2). Cells exposed to TGF-β1 to induce fibrogenesis were co-treated with crude KL extract and β-CIT. Gene expression was analyzed by Real-Time qRT-PCR to assess fibrosis-associated genes (ACTA2, COL1A1, TIMP1, SMAD2). The releasing of matrix metalloproteinase 9 (MMP-9) was measured by ELISA. Proteomic analysis and molecular docking identified potential signaling proteins and modeled protein-ligand interactions. Results showed that both crude KL extract and β-CIT suppressed HSC activation genes and MMP-9 levels. The MAPK signaling pathway emerged as a potential target of β-CIT. This study demonstrates the ability of KL extract and β-CIT to inhibit HSC activation during TGF-β1-induced fibrogenesis, suggesting a promising role of β-CIT in anti-hepatic fibrosis therapies.

Stabilization of a G-quadruplex (G4) in the promotor of the c-MYC proto-oncogene leads to inhibition of gene expression, and it thus represents a potentially attractive new strategy for cancer treatment. However, most G4 stabilizers show little selectivity among the many G4s present in the cellular complement of DNA and RNA. Intriguingly, a crescent-shaped cell-penetrating thiazole peptide, TH3, preferentially stabilizes the c-MYC G4 over other promotor G4s, but the mechanisms leading to this selective binding remain obscure. To investigate these mechanisms at the atomic level, we performed an in silico comparative investigation of the binding of TH3 and its analogue TH1 to the G4s from the promotors of c-MYC, c-KIT1, c-KIT2, and BCL2. Molecular docking and molecular dynamics simulations, combined with in-depth analyses of non-covalent interactions and bulk and per-nucleotide binding free energies, revealed that both TH3 and TH1 can induce the formation of a sandwich-like framework through stacking with both the top and bottom G-tetrads of the c-MYC G4 and the adjacent terminal capping nucleotides. This framework produces enhanced binding affinities for the c-MYC G4 relative to other promotor G4s, with TH3 exhibiting an outstanding binding priority. Van der Waals interactions were identified to be the key factor in complex formation in all cases. Collectively, our findings fully agree with available experimental data. Therefore, the identified mechanisms leading to specific binding of TH3 towards the c-MYC G4 provide valuable information to guide the development of new selective G4 stabilizers.

Eruca sativa is a commonly used edible plant in Italian cuisine. E. sativa 70% ethanol extract (ES) was fractionated with five organic solvents. Ethyl acetate fraction(EEA) had the highest antioxidant activity, which was correlated with the total polyphenol and flavonoid content. ES and EEA acted as PPAR-α ligands by PPAR-α competitive binding assay. EEA significantly increased cornified envelope formation as a keratinocyte terminal differentiation marker in HaCaT cells. Further, it significantly reduced nitric oxide and pro-inflammatory cytokines in lipopolysaccharide-stimulated RAW 264.7 cells. The main flavonol forms detected in high amounts from EEA are mono-, and di-glycoside of each aglycone. Flavonol mono-glycosides were shown to be a potent PPAR-α ligand using molecular docking simulation and showed the inhibition of nitric oxide. These results suggest that E. sativa is suitable for use in improving skin barrier function and inflammation in skin disorders, such as atopic dermatitis.

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.

The acetylcholinesterase-inhibitory potential of the oleanane-type triterpenes and their glycosides from the Terminalia arjuna (Combreatceae) bark, i.e. arjunic acid, arjunolic acid, arjungenin, arjunglucoside I, sericic acid, and arjunetin, is presented. The studies are based on the in silico pharmacokinetic and biomimetic studies, the acetylcholinesterase (AChE) inhibitory activity tests, and the molecular docking research. Based on the calculated pharmacokinetic parameters, arjunetin and arjunglucoside I are indicated as able to cross the blood-brain barrier. The compounds of interest exhibit marked acetylcholinesterase inhibitory potential, which was tested in the TLC bioautography test. The longest time to reach brain equilibrium is observed for both the arjunic and arjunolic acids and the shortest one for arjunetin. All compounds exhibit high and relatively similar magnitude of binding energies, varying from ca. -15 to -13 kcal/mol. The superposition of the most favorable positions of all ligands interacting with AChE is analyzed. The correlation between the experimentally determined IC50 values and the steric parameters of the molecules is investigated. The inhibition of the enzyme by the analyzed compounds shows their potential to be used as cognition enhancing agents. For the most potent compound (arjunglucoside I; ARG), the kinetics of AChE inhibition is tested. The Michaelis–Menten constant (Km) for the hydrolysis of the acetylthiocholine iodide substrate was calculated to be 0.011 mM.

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.

Cystic Fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the CFTR gene, coding for the CFTR chloride channel. About 10% of the CFTR gene mutations are "stop" mutations, which generate a Premature Termination Codon (PTC), thus synthesizing a truncated CFTR protein. A way to bypass PTC relies on ribosome readthrough, which is the ribosome’s capacity to skip a PTC, thus generating a full-length protein. “TRIDs” are molecules exerting ribosome readthrough; for some, the mechanism of action is still under debate. We investigate a possible mechanism of action (MOA) by which our recently synthesized TRIDs, namely NV848, NV914, and NV930, could exert their readthrough activity by in silico analysis and in vitro studies. Our results suggest a likely inhibition of FTSJ1, a tryptophan tRNA-specific 2’-O-methyltransferase.

Oyster mushroom( Pleurotus ostreatus) is belong to the group of healthy foods, as they contain high levels of proteins, vitamins and different classes of compounds, it is discovered that oyster mushrooms could play a key role in maintaining good health. Oyster mushroom (Pleurotus sp.) Class Basidiomycetes and Family Agaricaceae are widely known as ‘dhingri’ in India. Pleurotus Ostreatus have several medicinal properties including ; anti-arthritic , antitumor, immune modulatory , antioxidant, anticancer, anti-inflammatory, antigenotoxic, hypo-cholesterolaemic, antihyperglycaemic antihypertensive, antiplatelet aggregating, antiviral and antimicrobial activities.. In this paper studied that effects of chemical constituents of oyster mushroom(Pleurotus sp.) on DNA damaging protein which analyzed its activity of PARP inhibiting or vice – versa.For this analysis we choose the molecular docking technique to check the effects of different chemical constituents of oyster mushroom(Pleurotus sp.) on DNA damaging protein and compare their results to PARP inhibitory drugs which taken as standard . We perform the molecular docking in between chemical constituents of oyster mushroom(Pleurotus sp.) and 4UND protein compare to performance of molecular docking in between standard PARP inhibitory drugs and 4UND protein with the help of PyRx and BIOVIA Discovery studio software.The analysis of molecular docking shows that some chemical constituents of oyster mushroom(Pleurotus sp.) having more binding affinity than standard PARP inhibitory drugs .The Rutin shows better binding affinity than PARP inhibitory drugs on the same protein.

Medicinal plants possess a surplus of novel and biologically active secondary metabolites that are responsible for counteracting diseases. Traditionally, Gomphandra tetrandra (Wall.) Sleumer is used to treat mental disorders. The present research was designed to explore phytochemicals from the ethanol leaf extract of Gomphandra tetrandra (Wall.) Sleumer to identify the potential pharmacophore(s) in the treatment of neurological disorders. The chemical compounds of the experimental plant were identified through GC-MS analysis. Besides, in-vitro antioxidant activity was assessed using different methods. Furthermore, in-vivo neurological activity was assessed in Swiss-albino mice. Computer aided analysis was appraised to determine the best-fit phytoconstituent of a total of fifteen identified compounds in the experimental plant extract against beta-amyloid precursor protein. The experimental extract revealed fifteen compounds in GC-MS analysis and the highest content was 9, 12, 15-octadecatrienoic acid (Z, Z, Z). Also, the extract showed potent anti-oxidant activity in in-vitro assays. Furthermore, in in-vivo neurological assays, the extract disclosed significant (p<0.05) neurological activity. The most favorable phytochemicals as neurological agents were selected via ADMET profiling and molecular docking was studied with beta-amyloid precursor protein. Moreover, in the computer aided study, 1, 5-Diphenyl-2H-1, 2, 4-triazoline-3-thione (Pub Chem CID: 2802516) was more active than other identified compounds with strong binding affinity to beta-amyloid precursor protein. The present in vivo and in silico studies revealed neuropharmacological features of G. tetrandra leaves extract as a natural agent against neurological disorders, especially Alzheimer’s disease.

The investigation of membrane proteins, key constituents of cells, is hampered by the difficulty and complexity of their in vitro synthesis, of unpredictable yield. Cell-free synthesis is herein employed to unravel the impact of the expression construct on gene transcription and translation, without the complex regulatory mechanisms of cellular systems. Through the systematic design of plasmids in the immediacy of the start of the target gene, it was possible to identify translation initiation and the conformation of mRNA as the main factors governing the cell-free expression efficiency of the human voltage dependent anion channel (VDAC), a relevant membrane protein in drug-based therapy. A simple translation initiation model was developed to quantitatively assess the expression potential for the designed constructs. A scoring function is proposed that quantifies the feasibility of formation of the translation initiation complex through the ribosome-mRNA hybridization energy and the accessibility of the mRNA segment binding to the ribosome. The scoring function enables to optimize plasmid sequences and semi-quantitatively predict protein expression efficiencies. This scoring function is publicly available as webservice XenoExpressO at rna.tbi.univie.ac.at.

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).

Three finger toxins (3FTX) are a group of peptides that affect multiple receptor types. One group of proteins affected by 3FTX are nicotinic acetylcholine receptors (nAChR). Structural information on how neurotoxins interact with nAChR is limited and are confined to a small group of neurotoxins. Therefore, in silico methods are valuable in understanding the interactions between 3FTX and different nAChR subtypes, but there are no established protocols to model 3FTX – nAChR interactions. We developed a homology modeling and protein docking protocol to address this issue and tested its success on three different systems. First, neurotoxin peptides co-crystallized with acetylcholine binding protein (AChBP) were re-docked to assess whether Rosetta protein – protein docking can reproduce the native poses. Second, experimental data on peptide binding to AChBP was used to test whether the docking protocol can qualitatively distinguish AChBP-binders from non-binders. Finally, we docked eight peptides with known α7 and muscle-type nAChR binding properties to test whether the protocol can explain the differential activities of the peptides at the two receptor subtypes. Overall, our docking protocol succeeded in predicting both qualitative and specific aspects of 3FTX binding to nAChR and shed light on some unknown aspects of 3FTX binding to different receptor subtypes.

We use state-of-the-art computer-aided drug design (CADD) techniques to identify prospective inhibitors of the main protease enzyme, 3CLpro of the SARS-CoV-2 virus causing COVID-19. From our screening of over one million compounds including approved drugs, investigational drugs, natural products, and organic compounds, and a rescreening protocol incorporating enzyme dynamics via ensemble docking, we have been able to identify a range of prospective 3CLpro inhibitors. Importantly, some of the identified compounds had previously been reported to exhibit inhibitory activities against the 3CLpro enzyme of the closely related SARS-CoV virus. The top- ranking compounds are characterized by the presence of multiple bi- and monocyclic rings, many of them being heterocycles and aromatic, which are flexibly linked allowing the ligands to adapt to the geometry of the 3CLpro substrate site and involve a high amount of functional groups enabling hydrogen bond formation with surrounding amino acid residues, including the catalytic dyad residues H41 and C145. Among the top binding compounds we identified several tyrosine kinase inhibitors, which include a bioflavonoid, the group of natural products that binds best to 3CLpro. Another class of compounds that decently binds to the SARS-CoV-2 main protease are steroid hormones, which thus may be endogenous inhibitors and might provide an explanation for the age-dependent severity of COVID-19. Many of the compounds identified by our work show a considerably stronger binding than found for reference compounds with in vitro demonstrated 3CLpro inhibition and anticoronavirus activity. The compounds determined in this work thus represent a good starting point for the design of inhibitors of SARS-CoV-2 replication.

Three-dimensional structure of six closely related hydrogenases from purple bacteria has been modeled by combining template-based and ab initio modeling approach. The results lead to conclusion that there should be 4Fe3S-cluster in the structure of these enzymes. Thus, these hydrogenases could drive attention for exploring their oxygen tolerance and practical applicability in hydrogen fuel cells. Analysis of 4Fe3S-cluster's microenvironment showed intragroup heterogeneity. Possible function of the C-terminal part of the small subunit in membrane binding has been discussed. Comparison of the built models with existing hydrogenases of the same subgroup (membrane-bound oxygen-tolerant hydrogenases) has been carried out. Analysis of intramolecular interactions in the large subunits showed statistically reliable differences in number of hydrophobic interactions and number of ionic interactions. Molecular tunnels were mapped in the models and compared with structures from PDB. Protein-protein docking showed that these enzymes could exchange electrons in oligomeric state, which is important for oxygen-tolerant hydrogenases. Molecular docking with model electrode compounds showed mostly the same results as with hydrogenases from E.coli, H. marinus, R. eutropha, S. enterica; some interesting results were shown in case of HupSL from Rba. sphaeroides and Rvx. gelatinosus.

The objective of the this study was to reduce the benzo[a]pyrene-induced hepatotoxicity method in herbal medicine products and to give proof that neferine, daidzein, genistein possess antihepa-totoxic effects. B[a]P which classified as a group 1 carcinogen and metabolized to B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE) causes mutagenic DNA addition products. The reduc-tion of BPDE-DNA adduct formation by B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE) was derived by benzo[a]pyrene (B[a]P). In HepG2 cells, B[a]P exhibited toxicity and substance treatment of the cells with B[a]P with neferine in lotus and daidzein, genistein in soybean reduced the BPDE-DNA ad-ducts level. The level of B[a]P-metabolites in the substance treatment of the cells was presented that BPDE levels were reduced by neferine in lotus and daidzein, genisten in soybean. These results suggest that neferine in lotus and daidzein, genistein in soybean prevent B[a]P-induced hepato-toxicity for BPDE-DNA adduct formation.

BackgroundThe use of antimicrobials to treat food animals may result in antimicrobial residues in foodstuffs of animal origin. The European Medicines Association (EMA) and World Health Organization (WHO) define safe antimicrobial concentrations in food based on acceptable daily intakes (ADIs). It is unknown if ADI doses of antimicrobials in food could influence the antimicrobial susceptibility of human-associated bacteria. ObjectivesThis aim of this study was to evaluate if the consumption of ADI doses of erythromycin could select for erythromycin resistance in a Galleria mellonella model of Streptococcus pneumoniae infection. Methods A chronic model of S. pneumoniae infection in G. mellonella larvae was used for the experiment. Inoculation of larvae with S. pneumoniae was followed by injections of EMA (0.0875 μg/ml) and WHO (0.012 μg/ml) ADI doses of erythromycin proceeded by isolation of S. pneumoniae colonies on selective agar plates. Minimum inhibitory concentrations (MICs) of resistant colonies were measured, and whole genome sequencing (WGS) was performed followed by variant calling to determine the genetic modifications.   Results Exposure to single doses of both EMA and WHO ADI doses of erythromycin resulted in the emergence of erythromycin resistance in S. pneumoniae. Emergent resistance to erythromycin was associated with a mutation in rplA. Conclusion In our in vivo model, even single dose of erythromycin that are classified as acceptable by the WHO and EMA induced significant increases in erythromycin MICs in S. pneumoniae. These results suggest the need to include the induction of antimicrobial resistance (AMR) as a significant criterion for determining ADIs.

Exploring therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, a potent inhibitor targeting the SARS-CoV-2 Mpro, shows promise as an antiviral treatment. Additionally, Ivermectin, a broad-spectrum antiparasitic drug, has demonstrated effectiveness against the virus in laboratory settings. However, its clinical implications are still debated. Using computational methods such as molecular docking and 100 ns molecular dynamics simulations, we investigated how Nirmatrelvir and Ivermectin interact with SARS-CoV-2 Mpro(A). Calculations using density functional theory have been instrumental in elucidating the behavior of isolated molecules, primarily by analyzing the frontier molecular orbitals. Our analysis revealed distinct binding patterns: Nirmatrelvir formed strong interactions with amino acids like MET49, MET165, HIS41, HIS163, HIS164, PHE140, CYS145, GLU166, and ASN142, showing stable binding with a root mean square deviation (RMSD) of around 2.0 Å. On the other hand, Ivermectin interacted with THR237, THR239, LEU271, LEU272, and LEU287, displaying an RMSD of 1.87 Å, indicating enduring interactions. Both ligands stabilized Mpro(A), with Ivermectin showing stability and persistent interactions despite forming fewer hydrogen bonds. These findings offer detailed insights into how Nirmatrelvir and Ivermectin bind to the SARS-CoV-2 main protease, providing valuable information for potential therapeutic strategies against COVID-19.

The “circular bioeconomy” offers numerous opportunities for the health, cosmetic, and nutrition sectors through the potential reuse of Castanea sativa by-products. This abundant and sustainable resource provides valuable bioactive secondary metabolites with antioxidants and anti-inflammatory properties. The transformation of these by-products into high-value products for human health can contribute to sustainable economic growth and reduce the environmental impact of traditional waste disposal practices, thus creating added value from previously underutilized resources. In the present study, we investigated the antioxidant capacity, phytochemical composition and in vitro antioxidant and anti-inflammatory activity of C. sativa burrs (CSB) aqueous extract. The spectrophotometric study yielded optimal total phenolic content (TPC) values, along with significant antioxidant and anti-radical properties. The utilization of UPLC-MS-MS techniques for phytochemical investigation resulted in the identification of a total of 56 metabolites, providing confirmation of the presence of phenolic compounds in CSB. In addition, CSB significantly downregulated pro-inflammatory mediators in LPS-stimulated RAW 264.7 macrophage cells without significant cell toxicity.

A series of eight 5-nitrofuran-tagged oxazolyl tetrahydropyrazolopyridines (THPP’s) has been prepared in six stages with excellent regioselectivity. The testing of these compounds against pathogens of ESKAPE panel showed a good activity of lead compound 1-(2-methoxyethyl)-5-(5-nitro-2-furoyl)-3-(1,3-oxazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] pyridine (13g), which is superior to nitrofurantoin. These results confirmed the benefit of combining a THPP scaffold with a nitrofuran warhead. Certain structure-activity relationships were established in the course of this study which were rationalized by the induced-fit docking experiments in silico.

Different dopamine receptor (DR) subtypes are involved in pathophysiological conditions such as Parkinson´s Disease (PD), schizophrenia and depression. While many DR-targeting drugs have been approved by the FDA, only a very small number is truly selective for one of the DR subtypes. Additionally, most of them show promiscuous activity at related G-protein coupled receptors, thus suffering from diverse side-effect profiles. Multiple studies have shown that combined in silico / in vitro approaches are a valuable contribution to drug discovery processes. They can also be applied to divulge the mechanisms behind ligand selectivity. In this study, novel DR ligands were investigated in vitro to assess binding affinities at different DR subtypes. Thus, nine D2R/D3R-selective ligands (micro- to nanomolar binding affinities, D3R-selective profile) were successfully identified. The most promising ligand exerted nanomolar D3R activity (KI = 2.3 nM) with 263.7-fold D2R/D3R selectivity. Subsequently, ligand selectivity was rationalized in silico based on ligand interaction with a secondary binding pocket, supporting selectivity data determined in vitro. The developed workflow and identified ligands could aid in the further understanding of structural motifs responsible for DR subtype selectivity, thus, benefitting drug development in D2R/D3R-associated pathologies like PD.

Dysregulation of the arsenal of cells, growth factors, cytokines, proteases, and proteins involved in wound healing (WH), could delay the healing process. Plants and plant-derived molecules (PDMs) have been used as medicines for skin wounds. This study aimed to select and evaluate the pro-healing capacity of PMDs. Thirty-three PDMs and 10 therapeutic targets (TTs) were chosen for molecular docking and PDMs: aristolochic acid (AA), α-copaene, selinenes, β-caryophyllene (BC), and BCoxide, and TTs: metalloproteinase (MMP) 3, MMP13, and tumor necrosis factor (TNF α) for molecular dynamics. The bests inhibitor was AA, but because of its toxicity, BC and BCoxide were chosen for evaluation in HaCat cells and BALB/c mice excisional model. Both compounds were not toxic, and higher percentages of lesion area closure (LAC) were induced by BC treatment (p<0.05). All mice healed; however, an initial delay of LAC was induced by 0.05, 0.1% BCoxide, 0.1% BC, and allantoin. At the end of treatment, lower numbers of mast cells, level of cellular infiltrates (except 1% BCoxide and 0.05, 0.5%BC), epidermal thickness tendency (except 0.1, 0.5% BCoxide), and higher values of SC-thickness, and collagen fibers only by 0.5% BC treatment compared with untreated control (p<0.05) were observed. Our results show that BC is a promising multitarget candidate for wound healing treatment and optimization campaigns.

This research aims to find out whether the synthetic 1, 2, 4-triazine and its derivatives have antifungal effects and can protect humans from infection with Candida albicans. Molecular docking and molecular dynamic simulation are widely used in modern drug design to target a We are interested in using molecular docking and molecular dynamics modelling to investigate the interaction between the derivatives of 1, 2, 4-triazine and the resulting lanosterol 14 - demethylase (CYP51) of Candida albicans The inhibition of Candida albicans CYP51 is the main goal of our research. The 1, 2, 4-triazine and its derivatives have been docked to the CYP51 enzyme, which is involved in Candida albicans Multidrug Drug Resistance (MDR). Autodock tools were used to identifying the binding affinities of molecules against the target proteins. Compared to conventional fluconazole, the molecular docking results indicated that each drug has a high binding affinity for CYP51 proteins and forms unbound interactions and hydrogen bonds with their active residues and surrounding allosteric residues. The docking contacts were made using a 10 ns MD simulation with nine molecules. RMSD, RMSF, hydrogen bonds, and the Rg all confirm these conclusions. In addition, these compounds were expected to have a favorable pharmacological profile and low toxicity. The compounds are being offered as scaffolds for the development of new antifungal drugs and as candidates for future in vitro testing.

COVID-19 has emerged as deadly pandemic worldwide with no vaccine or suitable antiviral drugs to prevent or cure the disease. Because of the time-consuming process to develop new vaccines or antiviral agents, there has been a growing interest in repurposing some existing drugs to combat SARS-CoV-2. Vitamin D is known to be protective against acute respiratory distress syndrome (ARDS), pneumonia and cytokine storm. Recently it has been used as a repurposed drug for the treatment of H5N1 virus-induced lung injury. Circumstantial evidences indicate that people with low level of vitamin D are more susceptible to SARS-CoV-2. Although, vitamin D was suggested to interfere with viral replication, its interaction with any SARS-CoV-2 protein is unexplored yet. Beside this, ivermectin, a well-known anti-parasitic agent, exhibits potent anti-viral activities in vitro against viruses such as HIV-1 and dengue. Very recently, ivermectin has been found to reduce viral load of SARS-CoV-2 in vitro. We have analyzed available structures of SARS-CoV-2 proteins to identify probable binding partner(s) of vitamin D and ivermectin through knowledge-based docking studies and figured out possible implication of their binding in SARS-CoV-2 infection. Our observations suggest that the non-structural protein nsp7 possesses a potential site to house 25-hydroxyvitamin D3 (VDY) or the active form of Vitamin D, calcitrol. Binding of vitamin D with nsp7 likely to hamper the formation of nsp7-nsp8 complex which is required to bind with RNA dependent RNA polymerase (RdRP), nsp12 for optimal function. On the other hand, potential binding site of ivermectin has been identified in the S2 subunit of trimeric spike(S) glycoprotein of SARS-CoV-2. We propose that deeply inserted mode of ivermectin binding at three inter-subunit junctions may restrict large scale conformational changes of S2 helices which is necessary for efficient fusion of viral and host membrane. Our study, therefore, opens up avenues for further investigations to consider vitamin D and ivermectin as potential drugs against SARS-CoV-2.

SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by WHO due to high mortality, high basic reproduction number and lack of clinically approved drugs and vaccines for COVID-19. The genomic sequence of the virus responsible for COVID-19, as well as the experimentally determined three dimensional structure of the Main protease (Mpro) are available. The reported structure of the target Mpro was utilized in this study to identify potential drugs for COVID-19 using molecular docking based virtual screening of all approved drugs. The results of this study confirm preliminary reports that some of the drugs approved for treatment of other viral infections have the potential for treatment of COVID-19. Selected antiviral drugs, approved for human therapeutic applications, were ranked for potential effectiveness against COVID-19, based on predicted binding energy to the target Mpro of SARS-CoV-2, and novel candidates for drug repurposing were identified in this study. In addition, potential mechanisms for beneficial off target effects of some drugs in clinical trials were identified by using molecular docking.

Single nucleotide polymorphisms (SNP) are associated with diseases and drug response variabilities in humans. Elucidating the damaging and disease-associated SNPs using wet-laboratory approaches can be challenging and resource-demanding due to the large number of SNPs in the human genome. Due to the growth in the field of computational biology and bioinformatics, algorithms have been developed to help screen and filter out the most deleterious SNPs that are worth considering for wet-laboratory studies. Here we review the existing in-silico based methods used to predict and characterize the effects of SNPs on protein structure and function. This cutting-edge approach will facilitate the search for novel therapeutics, help understand the etiology of diseases and fast-track the personalized medicine agenda.

Recently, Gohar et al. introduced a novel, local, and well-behaved fractional calculus. It possesses all the classical properties, and Its locality imposes simplicity and accuracy in modeling fractional order systems. In this article, we further develop the definitions and extend the classical properties of Gohar fractional calculus to address some of the open problems in Calculus. The fractional Gronwall's integral inequality, Taylor power series expansion, and Laplace transform are defined and applied to overcome some of the limitations in the classical integer-order calculus. The fractional Laplace transform is applied to solve Bernoulli-type logistic and Bertalanffy nonlinear fractional differential equations, and the criteria under which it can be applied to solve linear differential equations are investigated.

Throughout this paper the impact of anxiety on adolescent athlete’s is highlighted through analyzing neurological and psychological aspects involved in sports performance. The neuroanatomy and neuropsychology of the human brain plays a major role in developing athlete’s that has only begun to be analyzed within recent years. Especially in young athletes, there are numerous factors that affect performance on the field that originate from the environment and training the adolescent athlete is involved in. Sports performance is viewed as a major physical factor such as training and lifting weights, however the psychological aspect of sports performance often goes unnoticed. Athletes can begin to develop mental fatigue and anxiety which inevitably can decrease their ability to perform. The athlete’s internal suffering begins to go unnoticed, as the only tangible factor is watching their performance decrease. This causes the athlete to push themselves further in training resulting in greater mental fatigue. This paper emphasizes the numerous factors neurologically that play a role in athletic performance which should be focused on in adolescent athletes as they navigate the challenges and competition that are apparent within athletics. It is critical to understand the processes and hormonal changes the body undergoes with training and playing a sport, this information can change the way adolescent sports are approached and advanced.

The resistance of Candida spp to fluconazole is a serious problem; Therefore, it must be investigated to expand the understanding of the phenomenon with a view to its clinical applicability. The aim was to evaluate the expression of ERG3, ERG11, CDR1, and SNQ2 genes involving computational analysis. Relative expression was quantified by RT-qPCR. Metrics were obtained by molecular docking and through Fisher's discriminant functions, a predictive classification against susceptibility to fluconazole was performed. The expression of ERG3, CDR1, and SNQ2 genes was higher in resistant strains than in dose-dependent sensitive strains. The gene with the highest expression in strains exposed to fluconazole was CDR1 and, in both resistant and dose-dependent sensitive strains exposed to fluconazole, the ERG11 gene had lower expression. The molecular docking model generated lower median fluconazole-ERG11 contacts than the median fluconazole-ERG3, -CDR1, and -SNQ2 contacts. The predicted classification through the multivariate model for fluconazole sensitivity obtained an accuracy of 73.5%. Resistant strains had a significant expression of CDR1, SNQ2 and ERG3 genes, compared to a comparatively low expression of ERG11. Molecular analysis identified a low affinity between fluconazole and its drug target, which may explain a lower intrinsic susceptibility of the fungus.

The expression of the Fasciola hepatica Carboxylesterase type B (CestB) gene is induced in response to the anthelmintic triclabendazole (TCBZ), resulting in a significant increase in enzymatic specific activity. Furthermore, the amino acid sequence of CestB exhibits variations that could lead to substantial amino acid substitutions at the ligand-binding site. These substitutions have the potential to affect the interaction between the ligand and the protein, as well as the catalytic properties of the enzyme. The objective of this study was to identify new CestB polymorphisms in TCBZ-resistant parasites using 3D modeling against the metabolically oxidized form of the anthelmintic TCBZSOX. Our aim was to observe the formation of TCBZSOX-specific binding pockets that could potentially explain the resistance to anthelmintic agents. We identified a CestB polymorphism in a TCBZ-resistant strain of parasites exhibiting three radical amino acid substitutions at positions 147, 215, and 243, resulting in the formation of a TCBZSOX-affinity pocket capable of binding the anthelmintic drug. Additionally, our 3D modeling analysis revealed that these amino acid substitutions also had an impact on the configuration of the CestB catalytic site, affecting the enzyme's interaction with chromogenic carboxylic ester substrates and altering its catalytic properties; however, the identified TCBZSOX-binding pocket was located far from the enzyme's catalytic site, making the enzymatic hydrolysis of TCBZSOX theoretically impossible. Nonetheless, the increased affinity for the anthelmintic may explain a drug-sequestration type of anthelmintic resistance and lays the foundation for the development of a molecular diagnostic tool for identifying anthelmintic resistance in F. hepatica.

Mincle, a C-type lectin, is expressed predominantly in macrophages, where it plays a role in the macrophage response to various microorganisms such as mycobacteria. Docking is a computational procedure in which various software packages generate different positions at which ligands bind to their receptors. Discovery Studio docking was used in Molegro Virtual Studios. ChemDraw and ChemDraw3D were used for ligand preparation and construction because the protein preparation performed using docking software was a very lengthy process. Mincle plays a novel and non-redundant role in the induction of inflammatory signaling in response to mycobacteria. One disadvantage of Molegro studio docking is that it does not show the metallic atoms with which it interacts but rather shows hydrogen bonding and amino acid interactions. Hypothetically, trehalose dimycolate (TDM) and trehalose dibenzenate (TDB) detected by macrophages ultimately lead to CARD9 signaling, thereby producing pro-inflammatory cytokines and chemokines that have the potential to be used therapeutically.

The most widely spread and neglected zoonotic disease – Leptospirosis, with an estimated 1.03 million cases and 58,900 deaths occurring annually, is a concern and can be prevented only by effective immunization. Due to the urgent need for a novel vaccine, various research organizations have been evaluating the protective immune response elicited by recombinant vaccines. In this study amino-acid sequences of Outermembrane protein (OMPL) 1, LipL 32, 41 and 46 from ten pathogenic serovars of Leptospira were selected to obtain epitopes that induce CD4+ and CD8+ T cell responses by binding to the MHC molecules. These B cell and T cell epitopes were used to design multi-epitope vaccine to which an adjuvant sequence was added at the N-terminal end and appropriate linkers were used to join the different epitopes to increase the efficiency of the vaccine constructs. Using an immuno-informatics approach, constructs were analyzed for the physiochemical properties, secondary and tertiary structure and its validation, docking with different receptors and prediction of binding affinity for each docked complex, followed by molecular dynamics simulation. Taking in consideration all the results, multi-epitope constructs designed may prove to be promising vaccine candidates against Leptospirosis and warrants experimental validation.

The recent outbreak of coronavirus disease 2019 caused by the new coronavirus, SARS-CoV-2, has become an international emergency. Since there is no effective therapy for the treatment of this disease, drugs or vaccine that can prevent or cure the SARS-CoV-2 infection are urgently needed. The viral 3-chymotrypsin-like cysteine protease (3CLpro), which plays a key role in the replication of coronavirus, is a potential drug target for the development of anti-SARS-CoV-2 drugs. With the crystal structure of 3CLpro, we performed virtual screening from a small chemical library of a Traditional Chinese Medicine recipe- FuFang Zhenzhu Tiaozhi (FTZ). Five compounds with the best scores were screened and could be considered as potential hit compounds to be investigated further with bioassays for their anti-virus effects.

Improper lifting measures of long-span spatial steel structures during construction process may delay the construction period and even cause safety accidents. Few studies on long-span spatial steel structures considered time-varying mechanical characteristic during construction process. In order to achieve safe and efficient installation in a long-span spatial steel structure, this research presents a time-varying mechanical analysis of the synchronous and asynchronous integral lifting and a single and interlaced point’s asynchronous integral lifting analysis method of a long-span spatial steel structure. The results showed that in the case of asynchronous lifting of single point, the displacement influence on other members is related to the distance. The closer the distance from the lifting point, the greater the influence. In asynchronous integral lifting, the lifting point with large lifting force is first installed to the specified position, and the lifting point with small lifting force is installed to the specified position.

In our recent publications, based on strong and electroweak interactions, we have developed a completely new formula for estimating nuclear binding energy. With reference to currently believed Semi Empirical Mass Formula (SEMF), we call our formula as ‘Strong and Electroweak Mass Formula’ (SEWMF). Our formula constitutes 4 simple terms and only one energy coefficient of magnitude 10.1 MeV. First term is a volume term, second term seems to be a representation of free nucleons associated with electroweak interaction, third term is a radial term and fourth one is an asymmetry term about the mean stable mass number. In this paper, we make an attempt to understand and estimate the maximum binding energy associated with any mass number. It can be expressed as, for A > 4, $\left(BE\right)_A\cong \left[A-0.000935A^2-A^{1/3}-A^{-1/2}\right]$ MeV. We are working on refining the 4^th term with even-odd corrections, shell corrections and other microscopic corrections. Proceeding further, stable mass numbers and super heavy mass numbers can be understood with a relation of the form, $\left[\textrm{RoundOff}\left(\left(Z+2.9464\right)^{1.2}-1.7165\right)\right]\pm\left[0,1\right]\pm\left(2n\right)$ where $n \cong 0,1,2$. It needs a review with respect to even-odd proton numbers and other microscopic corrections.

Peptide/Histidine Transporter PHT1 (SLC15A4) is expressed in lysosomal membranes of immune cells where it plays an important role in metabolic and inflammatory signaling. PHT1 is an H+-coupled/histidine symporter that can transport a broad range of oligopeptides, including a variety of bacterial-derived peptides. Moreover, it enables the scaffolding of various metabolic signaling molecules and interacts with key regulatory elements of the immune response. Therefore, it is not surprising that PHT1 is associated with the development of autoimmune diseases, such as systemic lupus erythematosus (SLE). Unfortunately, the pharmacological development of PHT1 has been hampered by the lack of appropriate transport assays. With the aim to address this shortcoming, a novel transport assay based on solid supported membrane-based electrophysiology (SSME) is presented. Key findings of the present SSME studies include the first recordings of electrophysiological properties, a pH dependence analysis, an assessment of PHT1 substrate selectivity, as well as the transport kinetics of the identified substrates. In contrast to previous works, PHT1 is studied its native lysosomal environment. Moreover, observed substrate selectivity is validated by molecular docking. Overall, this new SSME-based assay is expected to contribute to unlock the pharmacological potential of PHT1 and to deepen the understanding of its functional properties.

Covid-19 is one of humanity’s biggest threat in the 21st century with WHO figures reporting 636 million cases and up to 6.6 million deaths globally. SARS-CoV-2, the virus that causes the Covid-19 disease, is characterized by high mutation which contributes to its rapid spread. While several vaccines have been produced to minimize the severity of the coronavirus and diverse treatment regimens have been approved by the US FDA under Emergency Use Authorization (EUA), SARS-CoV-2 viral mutations continue to derail the efforts of scientists as the emerging variants evade the recommended therapies. Nonetheless, diverse computational models exist that offer an opportunity to overcome the barriers involved in developing new drugs. In this review, the focus is on the use of various virtual screening techniques like molecular docking, molecular dynamics simulations, QSAR, pharmacophore modeling, and homology modeling in repurposing SARS-CoV-2 therapeutics. The results have been promising from the computer-aided drug design (CADD) studies in suggesting potential compounds for treatment of Covid-19 and helping in bringing the pandemic under control.

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.

The cardiac sodium ion channel (NaV1.5) is a protein with four domains (DI-DIV), each with six transmembrane segments. Its opening and subsequent inactivation results in the brief rapid influx of Na+ ions resulting in the depolarization of cardiomyocytes. The neurotoxin veratridine (VTD) inhibits NaV1.5 inactivation resulting in longer channel opening times, and potentially fatal action potential prolongation. VTD is predicted to bind at the channel pore, but alternative binding sites have not been ruled out. To determine the binding site of VTD on NaV1.5, we performed docking calculations and high-throughput electrophysiology experiments. The docking calculations identified two distinct binding regions. The first site was in the pore, close to the binding site of NaV1.4 and NaV1.5 blocking drugs in experimental structures. The second site was at the “mouth” of the pore at the cytosolic side, partly solvent-exposed. Mutations at this site (L409, E417, and I1466) had large effects on VTD binding, while residues deeper in the pore had no effect, consistent with VTD binding at the mouth site. Overall, our results suggest a VTD binding site close to the cytoplasmic mouth of the channel pore. Binding at this alternative site might indicate an allosteric inactivation mechanism for VTD at NaV1.5.

Plasmodium falciparum dihydroorotate dehydrogenase (PfDODH) is one of the enzymes currently explored in the treatment of malaria. Although there is currently no clinically approved drug targeting PfDODH, many of the compounds in clinical trials have [1, 2, 4,] triazolo [1, 5-a] pyrimidin-7-amine backbone structure. This study sought to design new compounds from the fragments of known experimental inhibitors of PfDODH. Nine experimental compounds retrieved from Drug Bank online were downloaded and broken into fragments using Schrodinger power shell; the fragments were recombined to generate new ligand structures using BREED algorithm. The new compounds were docked with PfDODH crystal structure, after which the compounds were filtered with extensive drug-likeness and toxicity parameters. A 2D-QSAR model was built using the multiple linear regression method and externally validated. The compounds electronic behaviours were studied using DFT calculations. Structural investigation of the six designed compounds, which had lower binding energies than the standard inhibitors, showed that five of them had [1, 2, 4,] triazolo [1, 5-a] pyrimidin-7-amine moieties and interacted with essential residues at the PfDODH binding site. In addition to their drug-like and pharmacokinetic properties, they also showed minimal toxicities. The externally validated 2D-QSAR model with R² and Q² values of 0.6852 and 0.6691, confirmed the inhibitory prowess of these compounds against PfDODH. The DFT calculations showed regions of the molecules prone to electrophilic and nucleophilic attack. The current study thus provides insight into the development of a new set of potent PfDODH inhibitors.

Drug repurposing, the practice of utilizing existing drugs for novel clinical indications, has tremendous potential for improving human health outcomes and increasing therapeutic development efficiency. The goal of multidisease multitarget drug repurposing, also known as shotgun drug repurposing, is to develop platforms that assess the therapeutic potential of each existing drug for every clinical indication. Our Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun multitarget repurposing implements several pipelines via large scale modelling and simulation of interactions between comprehensive libraries of drugs/compounds and protein structures. In these pipelines, each drug is described by an interaction signature that is then compared to all other signatures that are then sorted and ranked based on similarity. Pipelines within the platform are benchmarked based on their ability to recover known drugs for all indications in our library, and predictions are generated based on the hypothesis that (novel) drugs with similar signatures may be repurposed for the same indication(s). The drug-protein interactions in the platform used to create the drug-proteome signatures may be determined by any screening or docking method but the primary approach used thus far has been an in house similarity docking protocol. In this study, we calculated drug-proteome interaction signatures using the publicly available molecular docking method Autodock Vina and created hybrid decision tree pipelines that combined our original bio- and cheminformatic approach with the goal of assessing and benchmarking their drug repurposing capabilities and performance. The hybrid decision tree pipeline outperformed the corresponding two docking-based pipelines it was synthesized from, yielding an average indication accuracy of 13.3% at the top10 cutoff (the most stringent), relative to 10.9% and 7.1% for its constituent pipelines, and a random control accuracy of 2.2%. We demonstrate that docking based virtual screening pipelines have unique performance characteristics and that the CANDO shotgun repurposing paradigm is not dependent on a specific docking method. Our results also provide further evidence that multiple CANDO pipelines can be synthesized to enhance drug repurposing predictive capability relative to their constituent pipelines. Overall, this study indicates that pipelines consisting of varied docking based signature generation methods can capture unique and useful signal for accurate comparison of drug-proteome interaction signatures, leading to improvements in the benchmarking and predictive performance of the CANDO shotgun drug repurposing platform.

The development of microbial products for cancer treatment has been in the spotlight in recent years. In order to accelerate the lengthy and expensive drug development process, in silico screening tools are systematically employed, especially during the initial discovery phase. Moreover, considering the steadily increasing number of molecules approved by authorities for commercial use, there is a demand for faster methods to repurpose such drugs. Here we present a review on virtual screening web tools, publicly available databases of molecular targets and libraries of ligands, with the aim to facilitate the discovery of potential anticancer drugs based on microbial products. We provide an entry-level step-by-step description of the workflow for virtual screening of microbial metabolites with known protein targets, as well as two practical examples using freely available web tools. The first case presents a virtual screening study of drugs developed from microbial products using Caver Web, a web tool that performs docking along a tunnel. The second case comprises a comparative analysis between a healthy isocitrate dehydrogenase 1, a mutant that results in cancer, using the recently developed web tool PredictSNP^Onco. In summary, this review provides the basic and essential background information necessary for virtual screening experiments, which may accelerate the discovery of novel anticancer drugs.

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.

Many neurodegenerative diseases are directly related to the formation of toxic protein aggregates, such as Parkinson’s and Alzheimer’s diseases, which are associated with the aggregation of alpha-synuclein (α-syn) and beta-amyloid (Aβ ), respectively. In this context, protein fibrils are the hallmark of these neurodegenerative diseases. In this sense, planning or designing compounds that are capable of preventing or reducing the formation of protein aggregation in the brain can be of fundamental importance for the curative treatment of these diseases. This work presents an in silico and experimental study to investigate the inhibitory potential of the ligands Octovespin (bioinspired by the wasp venom Polybia Occidentalis) and Fraternine-10 (bioinspired by the wasp venom Parachartergus fraternus wasp) against the aggregation of fibrils of the peptides Aβ(17-42) and α-syn, respectively. Using molecular docking and molecular dynamics simulations with 100 ns, the disaggregation capacity of these ligands was studied. The results obtained indicate that Octovespin and Fraternine-10 interact with the Aβ and α-syn protein fibrils throughout the simulation time. The RMSD values and the interactions with amino acids responsible for fibril aggregation demonstrate that both Octovespin and Fraternine-10 have a significant disaggregation potential, which corroborates the observations in vitro and in vivo. Furthermore, experimental results of Fraternine-10 demonstrate an anti-aggregation effect, indicating that it can promote the disaggregation of fibrils and prevent them from aggregating again to form oligomers. These discoveries qualify these molecules as potential candidates to become medicines against Parkinson’s and Alzheimer’s diseases.

During COVID-19 pandemic, drug repurposing represented an effective strategy to obtain quick answers to medical emergencies. Basing on previous data on Methotrexate (MTX), we evaluated the anti-viral activity of several DHFR inhibitors in two cell lines. We observed that this class of compounds showed a significant influence on the virus-induced cytopathic effect (CPE) partly associated to the intrinsic antimetabolic activity of these drugs, but also to a specific antiviral function. To elucidate the molecular mechanisms, we took advantage of our EXSCALATE platform for in-silico molecular modelling and further validated the influence of these inhibitors on nsp13 and viral entry. Interestingly, Pralatrexate and Trimetrexate showed superior effects in counteracting the viral infection compared to other DHFR inhibitors. Our results indicate that their higher activity is due to their polypharmacological and pleiotropic profile. These compounds can thus potentially give a clinical advantage in the management of SARS-CoV-2 infection in patients already treated with this class of drugs.

Alpha-fetoprotein (AFP) is a major embryo- and tumor-associated protein capable of binding and transporting variety of hydrophobic ligands including estrogens. AFP has been shown to inhibit estrogen receptor (ER)-positive tumor growth and this can be attributed to its estrogen-binding ability. Despite AFP has long been investigated, its three-dimensional (3D) structure has not been experimentally resolved and molecular mechanisms underlying AFP-ligand interaction remain obscure. In our study we constructed homology-based 3D model of human AFP (HAFP) with the purpose to perform docking of ERα ligands, three agonists (17β-estradiol, estrone and diethylstilbestrol) and three antagonists (tamoxifen, afimoxifene and endoxifen) into the obtained structure. Based on ligand docked scoring function, we identified three putative estrogen- and antiestrogen-binding sites with different ligand binding affinities. Two high-affinity sites were located in (i) a tunnel formed within HAFP subdomains IB and IIA and (ii) opposite side of the molecule in a groove originating from cavity formed between domains I and III, while (iii) the third low-affinity site was found at the bottom of the cavity. 100 ns MD simulation allowed studying their geometries and showed that HAFP-estrogen interactions occur due to van der Waals forces, while both hydrophobic and electrostatic interactions were almost equally involved in HAFP-antiestrogen binding. MM/GBSA rescoring method estimated binding free energies (ΔG_bind) and showed that antiestrogens have higher affinities to HAFP as compared to estrogens. We performed in silico point substitutions of amino acid residues to confirm their roles in HAFP-ligand interactions and showed that Thr132, Leu138, His170, Phe172, Ser217, Gln221, His266, His316, Lys453, and Asp478 residues along two disulfide bonds, Cys224-Cys270 and Cys269-Cys277 have key roles in both HAFP-estrogen and HAFP-antiestrogen binding. Data obtained in our study contribute to understanding mechanisms underlying protein-ligand interactions and anti-cancer therapy strategies based on ER-binding ligands.

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.

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.

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.

The approval of sucrose fatty acid esters (SFAEs) as food additives/preservatives has triggered enormous interest in discovering new applications for these materials. Accordingly, many researchers reported that SFAEs consist of various sugar moieties, and hydrophobic side chains are highly active against certain fungal species. The combination of chain length and site of acylation is crucial in endowing the SFAE with high antimicrobial potency against Aspergillus species. Following several important studies, we herein present the synthesis and an assessment of the effects of acylation site and chain length (i.e., C-6 vs. C-2, C-3, C-4, and long-chain vs. short-chain) on the antimicrobial activity of mannopyranoside fatty acid esters. In vitro tests revealed that the fatty acid chain length in mannopyranoside esters significantly affects the antifungal activity where C12 chains are more potent against Aspergillus species. In terms of acylation site, mannopyranoside esters with a C8 chain substituted at the C-6 position are more active in antifungal inhibition. Molecular docking also revealed that these mannopyranoside esters had comparatively better stable binding energy, and hence better inhibition, with the fungal enzymes lanosterol 14-alpha-demethylase (3LD6), urate oxidase (1R51), and glucoamylase (1KUL) than the standard antifungal drug fluconazole. Additionally, the thermodynamic, orbital, drug-likeness, and safety profiles of these mannopyranoside esters were calculated and discussed, along with the structure-activity relationships (SAR). This study thus highlights the importance of the acylation site and lipid-like fatty acid chain length that govern the antimicrobial activity of mannopyranoside-based SFAE.

The emergence of SARS/MERS drug resistant COVID-19 with high transmission and mortality has recently been declared a deadly pandemic causing economic chaos and significant health problems. Like all coronaviruses, SARS-CoV-2 is a large virus that has many druggable components within its proteome. In this study, we focused on repurposing approved and investigational drugs by identifying potential drugs that are predicted to effectively inhibit critical enzymes within SARS-CoV-2. We shortlisted seven target proteins with enzymatic activities known to be essential at different stages of the virus life cycle. For virtual screening, the energy minimization of a crystal structure or modeled protein was carried out using Protein Preparation Wizard (Schrödinger LLC, 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs (n=5903) that are already approved by worldwide regulatory bodies including the FDA, using the ZINC database. Screening was performed against viral targets using three sequential docking modes (i.e. HTVS, SP and XP). Our in-silico virtual screening identified ~290 potential drugs based on the criteria of energy, docking parameters, ligand and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. A top lead from each target group was further subjected to molecular dynamics simulation (MDS) using the Desmond module to validate the efficacy of the screening pipeline. All of the simulated hit-target complexes were predicted to strongly interact and with highly stable binding. Thus, we have identified a number of approved and investigational drugs with high likelihood of inhibiting a variety of key SARS-CoV-2 proteins. Follow-up studies will continue to identify inhibitors suitable for combination therapy based on drug-drug synergy to thwart resistance. In addition, the screening hits that we have identified provide excellent probes for understanding the binding properties of the active sites of all seven targets, further enabling us to derive consensus molecules through computer-aided drug design (CADD). While infections are expanding at a rampant pace, it must be recognized that resistance will grow commensurately through either genetic shift and/or genetic drift to all small molecule drugs identified. Vaccines should provide a more permanent solution through prevention, but resistivity is still a possible scenario. Nevertheless, a persistent multi-target drug development program is essential to curb this ongoing pandemic and to keep reemergence in check.

The novel coronavirus COVID- 19 disease is extremely contagious and has been spread worldwide. First COVID-19 case was identified in December, 2019 and within three months, more than one million affected cases and over 65,000 deaths have been reported. SARS-coronavirus 2 (SARS-CoV-2) also known as 2019-nCoV is a causative agent of COVID-19 disease and belongs to the SARS CoV (Severe Acute Respiratory Syndrome corona virus) family. The SARS-CoV-2 enters the human body by binding its viral surface spike protein with the host angiotensin-converting enzyme 2 (ACE2) receptors and cause infection. To prevent the virus entry and its transmission in the human body, we focused on the two domains of ACE2: i) the N-terminal extracellular binding domain (18-740 residues) reported for coronavirus spike interaction, and ii) the C-terminal cytoplasmic region (762-805 residues) to prevent the virus transmission. Therefore, we proposed: i) inhibition of receptor binding domain (RBD) of SARS-CoV-2 and human ACE2 protein may prevent the virus entry to the host and ii) inhibition of phosphorylation at Ser-787 of ACE2 protein may prevent the transmission of the virus in the COVID-19 patients. In the past, the critical role of Ser 787 in human ACE2 protein has been experimentally verified in SARS-CoV transmission, that upon binding to the receptor, SARS- CoV induces CKII- mediated phosphorylation of ACE2 at Ser-787 that in-turn facilitate virus entry to host cells, followed by replication and activation of ACE2, initiates downstream signaling leading to lung fibrosis. Therefore, in this study, we have suggested post-translational modification (PTM) O-β-GlcNAcylation, and two compounds Chloroquine and 2-hydroxybenzohydrazine might share the common pathways to prevent the COVID-19 infection in human. The addition of O-β-GlcNAcylation at same or neighboring Ser/ Thr residues results in phosphorylation inhibition and a change in protein structural and functional confirmations. Thereby, using neural networking methods, we have identified Ser/ Thr residues in ACE2 that are potential sites for phosphorylation and / or O-β-GlcNAcylation. Molecular docking showed that UDP-GlcNAc has more binding affinity with Ser-787 than the phosphoryl group. Moreover, chloroquine and 2-hydroxybenzohydrazine also showed great potential to bind at Ser-787 that may result in inhibition of Ser-787 phosphorylation and downstream signaling. Furthermore, O-β-GlcNAcylation, chloroquine and 2-hydroxybenzohydrazine showed their high affinity at ACE2-SARS-CoV-2receptor binding domain that may prevent the entry of SARS-CoV-2 into human body. In conclusion, inhibition of human ACE2 phosphorylation at Ser-787 and ACE2-SARS-CoV-2 binding domain could be promising targets against SARS-CoV-2 infection.

In this work we discuss the insights from activity landscape, docking and molecular dynamics towards the understanding of the structure-activity relationships of dual inhibitors of major epigenetic targets: lysine metiltransferase (G9a) and DNA metiltranferase 1 (DNMT1). The study was based on a novel data set of 50 published compounds with reported experimental activity for both targets. The activity landscape analysis revealed the presence of activity cliffs, e.g., pairs of compounds with high structure similarity but large activity difference. Activity cliffs were further rationalized at the molecular level by means of molecular docking and dynamics simulations that led to the identification of interactions with key residues involved in the dual activity or selectivity with the epigenetic targets.

Gilbert's syndrome (GS) is a common hereditary condition characterized by mild increases in serum bilirubin levels due to inherited defects in bilirubin metabolism. This review, based on data from peer-reviewed articles and journals spanning from 1977 to January 2024, provides a comprehensive overview of over four decades of research on GS. Early studies primarily focused on defining the clinical and genetic characteristics of the syndrome, laying the foundation for subsequent investigations. More recent research has delved into the genetic mechanisms underlying the reduced expression of bilirubin UDP-glucuronosyltransferase, which has significantly enhanced our understanding of the pathogenesis of GS. Furthermore, recent studies have shed light on the clinical implications of GS, including its association with non-alcoholic fatty liver disease and mortality risk, highlighting the complex interplay between genetic factors, bilirubin metabolism, and clinical outcomes. Despite its generally benign nature, thorough research is essential to fully understand the impact of GS on patients' lives. This review emphasizes the importance of ongoing research to deepen our understanding of GS and its broader implications.

Since the beginning of the COVID-19 pandemic, extensive drug repurposing efforts sought to identify small molecule antivirals with various mechanisms of action. Here we aim to review research progress on small molecule viral entry and fusion inhibitors that directly bind to the SARS CoV-2 Spike protein. Early in the pandemic, numerous small molecules were identified in drug repurposing screens and reported to be effective in vitro SARS CoV-2 viral entry or fusion inhibitors. However, given minimal experimental information regarding the exact location of small molecule binding sites on Spike, it was unclear what the specific mechanism of action was, or where the exact binding sites were on Spike for some inhibitor candidates. The work of countless researchers has yielded great progress, with the identification of many viral entry inhibitors that target elements on the S1 receptor binding domain (RBD) or N-terminal domain (NTD) and disrupt S1 receptor binding function. In this review, we will also focus on highlighting fusion inhibitors that target inhibition of the S2 fusion function, either by disrupting the formation of the postfusion S2 conformation or alternatively by stabilizing structural elements of the prefusion S2 conformation to prevent conformational changes associated with S2 function. We highlight experimentally validated binding sites on the S1/S2 interface and on the S2 subunit. While most mutations to the Spike protein to date in variants of concern (VOCs) have been localized to the S1 subunit, the S2 subunit sequence is more conserved with only a few observed mutations in proximity to S2 binding sites. Several recent small molecules targeting S2 have been shown to have robust activity over numerous recent VOC mutant strains and/or greater broad spectrum antiviral activity for other more distantly related coronaviruses.

In the dynamic landscape of drug discovery, Computer-rAided Drug Design (CADD) emerges as a transformative force, bridging the realms of biology and technology. This paper overviews CADD's historical evolution, categorization into structure-based and ligand-based approaches, and its crucial role in rationalizing and expediting drug discovery. As CADD advances, incorporating diverse biological data and ensuring data privacy become paramount. Challenges persist, demanding the optimization of algorithms and robust ethical frameworks. Integrating Machine Learning and Artificial Intelligence amplifies CADD's predictive capabilities, yet ethical considerations and scalability challenges linger. Collaborative efforts and global initiatives, exemplified by platforms like Open Source Malaria, underscore the democratization of drug discovery. The convergence of CADD with personalized medicine offers tailored therapeutic solutions, though ethical dilemmas and accessibility concerns must be navigated. Emerging technologies like quantum computing, immersive technologies, and green chemistry promise to redefine the future of CADD. The trajectory of CADD, marked by rapid advancements, anticipates challenges in ensuring accuracy, addressing biases in AI, and incorporating sustainability metrics. The paper concludes by highlighting the need for proactive measures in navigating the ethical, technological, and educational frontiers of CADD to shape a healthier, brighter future in drug discovery.

The paper introduces and describes the recent and still ongoing development activities performed in Luxembourg for In-Orbit Attach Mechanisms for (Drag) Sails Modules to be operated from Space Tugs. After some preparatory work aiming at understanding the possible operational aspects, three designs have been completed for their 3D (Metal and Plastic) Printing. The Plastic-printed prototype underwent a series of automated tests where a robotic arm, equipped with an advanced force sensor, replicated four docking scenarii in ideal and degraded modes. The observation of the forces and torques behaviors at and after impact allowed to characterize the typical patterns for the various contacts but also, to identify a type of impact potentially dramatic for the safety of the docking and its equipment: in case of off-axis approach, “point” contacts shall be avoided as they instantaneously transfer the total kinetic energy in a small area that could break.

A large body of evidence reports about the positive effects of physical activity in pathophysiological conditions associated with aging. Physical exercise, alone or in combination with other medical therapies, unquestionably causes reduction of symptoms in chronic non-transmissible diseases often leading to significant amelioration or complete healing. The molecular basis of this exciting outcome, however, remain largely obscure. Epigenetics, exploring at the interface between environmental signals and the remodelling of chromatin structure, promises to shed light on this intriguing matter possibly contributing to the identification of novel therapeutic targets. In this review, we shall focalize on the role of sirtuins (Sirts) a class III histone deacetylases (HDACs) which function has been frequently associated, often with a controversial role, to the pathogenesis of aging-associated pathophysiological conditions including cancer, cardiovascular, muscular, neurodegenerative, bones and respiratory diseases. Numerous studies, in fact, demonstrate that Sirt-dependent pathways are activated upon physical and cognitive exercises linking mitochondrial function, DNA structure remodelling and gene expression regulation to designed medical therapies leading to tangible beneficial outcomes. However, in similar conditions, other studies assign to sirtuins a negative pathophysiological role. In spite of this controversial effect, it is doubtless that studying sirtuins in chronic diseases might lead to an unprecedented improvement of life quality in the elderly.

The less virulent human (h) coronaviruses (CoVs) 229E, NL63, OC43, and HKU1 cause mild, self-limiting respiratory tract infections, while the more virulent SARS-CoV-1, MERS-CoV, and SARS-CoV-2 have caused severe outbreaks. The CoV envelope (E) protein, an important contributor to the pathogenesis of severe hCoVs infections, may provide insight into this disparate severity of the disease. We, therefore, generated full-length E protein models for SARS-CoV-1, -2, MERS-CoV, HCoV-229E, and HCoV-NL63 and docked C-terminal peptides of each model to the PDZ domain of the human PALS1 protein. The PDZ-binding motif (PBM) of the SARS-CoV-1, -2, and MERS-CoV models adopted a more flexible, extended coil while the HCoV-229E and HCoV-NL63 models adopted a less flexible alpha helix. All the E peptides docked to PALS1 occupied the same binding site and the more virulent hCoV E peptides generally interacted more stably with PALS1 than the less virulent ones. We propose that the increased flexibility of the PBM in more virulent hCoVs may permit more stable binding to various host proteins, thereby possibly contributing to more severe disease. This is the first paper to model full-length 3D structures for both more virulent and less virulent hCoVs E proteins, providing novel insights for possible drug and/or vaccine development.

Huperzine A is an herbal reversible inhibitor of Acetylcholinesterase (AChE). A molecular docking analysis on Huperzine A molecule has been carried out to understand its structure, conformational flexibility, intermolecular interaction and the binding affinity in the active site of AChE enzyme. Further, the charge density distribution of huperzine A molecule (lifted from the active site of AChE) was determined from the high level quantum chemical calculations coupled with charge density analysis. The binding affinity of Huperzine A towards AChE was calculated from the molecular docking; the lowest docked energy is -8.46 kcal/mol. In the active site, huperzine A molecule interacts with acyl binding pocket-Phe330 of AChE, that is, the bicyclo ring group of huperzine A forms an intermolecular interaction with the oxygen atom of main chain of the amino acid residue Phe330 at the distances 3.02 and 3.25 Å respectively. On the other hand, a gas phase study on huperzine A molecule also performed using HF and DFT (B3LYP) methods with the basis set 6-311G**. The molecular structure, conformation, and the charge density distribution of huperzine A molecule in the gas phase have determined using quantum chemical calculations and the charge density analysis. The comparative studies between the gas phase and the active site forms of huperzine A molecule, explicitly reveals the degree of conformational modification and the charge density redistribution of huperzine A when present in the active site. The dipole moment of the molecule in the active site is 6.85 D, which is slightly higher than its gas phase value (5.91 D). The electrostatic potential (ESP) surface of active site molecule clearly shows the strong electronegative and positive ESP regions of the molecule, which are the expected strong reactive locations of the molecule.

The document sets out three differentiated proposals for the transport of medicines through RPAS with their respective regulations, adapted to different operational categories: open category, special category and military scope. In the open category, an economical and efficient solution is prioritized for urban and rural areas, complying with weight and height regulations, in addition to guaranteeing the stability and quality of medications during transportation. The special category allows more complex operations and in more adverse conditions, such as densely populated areas and long routes, incorporating advanced security measures and training for personnel. In the military field, RPAS are used in conflict zones and hard-to-reach areas, ensuring the safe and rapid delivery of medical supplies under extreme conditions. Success stories in different countries are highlighted, demonstrating significant improvements in delivery times and risk reduction for health personnel.

We delve into the axion-dilaton model within the supergravity framework, with a specific focus on the intricacies of domain wall construction and stability. Employing holographic vitrification, we unravel the dynamics of domain wall formation in gauge theories featuring periodic vacuum structures. Our model, incorporating a QCD-like axion term and a stabilizing dilaton, undergoes scrutiny for conductivity variations under weak disorder. The investigation reveals the model's resilience, manifesting near-perfect conductivity under mild disorder conditions. However, the rigorous mathematical motivation for the holographic setup demands further elucidation. The scattered nature of our results prompts the necessity for a more systematic interpretation of QCD phenomena and conductivity transitions. This study contributes to the mathematical understanding of the axion-dilaton model's behavior, highlighting the imperative for a refined holographic framework and a more coherent interpretation of observed phenomena.

Candidiasis is considered an emerging public health concern because of the occurrence of drug-resistant Candida strains and the lack of available structurally diverse antifungal drug armamentariums. The indole alkaloid globospiramine from the anticandidal Philippine medicinal plant Voacanga globosa exhibits a variety of biological activities; however, its antifungal properties remain to be explored. In this study, we report the in vitro antifungal activities of globospiramine against Candida albicans and Candida tropicalis and explore its possible target proteins using in silico methods. The colony-forming unit (CFU) viability assay revealed time- and concentration-dependent anticandidal effects of the alkaloid by decreasing almost 50% of the viable CFUs 60 min after treatment. Results of the MIC and MFC assays indicated inhibitory and fungicidal effects of globospiramine against C. albicans (MIC = 8 µg/mL; MFC = 4 µg/mL) and potential fungistatic effects against C. tropicalis at lower concentrations (MIC = 4 µg/mL; MFC &gt; 64 µg/mL). The FAM-FLICA poly-caspase assay showed metacaspase activation in C. albicans cells at concentrations of 16 and 8 µg/mL, which agreed with the MIC and MFC values. Molecular docking and molecular dynamics simulation experiments indicated stable, strong binding of globospiramine with the target proteins 1,3-β-glucan synthase and Als3 adhesin enzymes, which are indirectly involved in apoptotic-driven candidal inhibition.

Clofazimine and Arbidol have both been reported to be effective in vitro SARS-CoV-2 fusion inhibitors. Both are promising drugs repurposed for treatment of COVID-19 and have been used in several previous and ongoing clinical trials. Small-molecule binding to expressed constructs of the trimeric S2 segment of Spike and the full-length SARS-CoV-2 spike protein were measured using a Surface Plasmon Resonance (SPR) binding assay. We demonstrate that Clofazimine, Toremifene, Arbidol and other Arbidol derivatives bind to the S2 segment of the Spike protein. Clofazimine provided the most reliable and highest quality SPR binding data to S2 over the conditions explored. A molecular docking approach was used to identify the most favorable binding sites on the S2 segment in the prefusion conformation, highlighting two possible small-molecule binding sites for fusion inhibitors. Results from molecular docking and modeling the structure-activity-relationship (SAR) of a newly reported series of Clofazimine derivatives supports the proposed Clofazimine binding site on the S2 segment. When the proposed Clofazimine binding site is superimposed with other experimentally determined coronavirus structures in structure-sequence alignments, the changes in sequence and structure may rationalize the broad-spectrum antiviral activity of Clofazimine in closely related coronavirus such as (SARS-CoV, MERS, hCoV-229E, hCoV-OC43).

As Chronic Non-Communicable Diseases (CNCD) increase, preventive approaches become more crucial. In this review, Calorie Restriction (CR) effects on human beings were evaluated, comparing benefits and risks of different CR diets: classic CR vs ketosis-inducing diets, including Intermittent Fasting (IF), Classic Ketogenic Diet (CKD), Fasting Mimicking Diet (FMD), Very-Low-Calorie Ketogenic Diet (VLCKD) and Spanish Ketogenic Mediterranean Diet (SKMD). Special emphasis on Insulin Resistance (IR) was placed, as it mediates Metabolic Syndrome (MS), a risk factor for CNCD, and predicts MS diagnosis. CR is the most robust intervention known to increase lifespan and health span, with high evidence and known biochemical mechanisms. CR improves cardiometabolic risk parameters, boosts exercise insulin sensitivity response, and there may be benefits of implementing moderate CR on healthy young and middle-aged individuals. However, there is insufficient evidence to support long-term CR. CKD is effective for weight and MS management, and may have additional benefits such as prevention of muscle loss and appetite control. SKMD has extreme significance benefits for all the metabolic parameters studied. Studies show inconsistent benefits of IF compared to classic CR. More studies are required to study biochemical parameters, reinforce evidence, identify risks, and seek effective and safe nutritional CR approaches.

Epoxy asphalt (EA) concrete is widely used in constructing long-span steel bridge pavements (SBDPs). This study aims to derive a fatigue damage evolution law, conducting an experimental investigation of SBDP. First, a general theoretical form of the fatigue damage evolution law of materials is established based on the thermal motion of atoms. Then, fatigue experiments demonstrate that this evolution law well represents the known damage–life relationships of SBDP. Taking into account the experimental relationships between damage and fatigue life under symmetrical cyclic loadings with different overload amplitudes and temperature variations, a detailed damage evolution law is deduced. Finally, the role of damage accumulation is discussed on the basis of the proposed damage evolution law for the extreme situation of heavy overload and severe environments. The results show that both heavy loading and falling temperatures increase the fatigue damage of SBDP considerably; therefore, SBDP should avoid heavy loading combined with winter temperatures. EA shows a fatigue life two to three times longer than that of modified matrix asphalt (SMA) or guss asphalt (GA). For the same thickness, EA pavement is demonstrated to be more suitable for an anti-fatigue design of large-span SBDP under high traffic flows and low temperatures.

Effective therapeutics for Alzheimer's disease (AD) are in great demand worldwide. In our previous work, we responded to this need by synthesizing novel drug candidates consisting of 4-amino-2,3-polymethylenequinolines conjugated with butylated hydroxytoluene via fixed-length alkylimine or alkylamine linkers (spacers) and studying their bioactivities pertaining to AD treatment. Here, we report significant extensions of these studies, including the use of variable-length spacers and more detailed biological characterizations. Conjugates were potent inhibitors of acetylcholinesterase (AChE, minimum IC50 15.1±0.2 nM) and butyrylcholinesterase (BChE, minimum IC50 5.96±0.58 nM), with weak inhibition of off-target carboxylesterase. Conjugates with alkylamine spacers were more effective cholinesterase inhibitors than alkylimine analogs. Optimal inhibition for AChE was exhibited by cyclohexaquinoline and for BChE by cycloheptaquinoline. Increasing spacer length elevated potency against both cholinesterases. Structure-activity relationships agreed with docking results. Mixed-type reversible AChE inhibition, dual docking to catalytic and peripheral anionic sites, and propidium iodide displacement suggested the potential of hybrids to block AChE-induced β-amyloid (Aβ) aggregation. Hybrids also exhibited inhibition of Aβ self-aggregation in the thioflavin test; those with a hexaquinoline ring and C8 spacer were the most active. Conjugates demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Quantum-chemical calculations explained antioxidant results. Computed ADMET profiles indicated favorable blood-brain barrier permeability suggesting CNS activity potential. Thus, the conjugates could be considered promising multifunctional agents for potential treatment of AD.

L-17 is a thiadiazine derivative with putative anti-inflammatory, neuroprotective, and antidepressant-like properties. In this study, we applied combined in silico and in vivo electrophysiology techniques to reveal the potential mechanism of action of L-17. PASS 10.4 Professional Extended software suggested that L-17 might have pro-cognitive, antidepressant, and antipsychotic effects. Docking energy assessment with AutoDockVina predicted that the binding affinities of L-17 to the serotonin transporter (SERT) and serotonin receptors 3 and 1A (5-HT3 and 5-HT1A) are compatible to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and selective antagonists of 5-HT3 and 5-HT1A receptors, granisetron and WAY100135, respectively. However, while the binding mechanisms of L-17 to the SERT and 5-HT1A receptor were similar to fluoxetine and WAY100135, its interacting with 5-HT3 receptor might be substantially different from this of granisetron. Acute administration of L-17 led to dose-dependent inhibition of firing activity of 5-HT neurons of the dorsal raphe nucleus. This inhibition was partially reversed by subsequent administration of WAY100135. Based on both in silico and in vivo electrophysiology assessments, we suggest that L-17 is a potent 5-HT reuptake inhibitor and a putative partial agonist of 5-HT1A receptors. As such, L-17 in particular and thiadiazine derivatives, in general, might be a representative of a new class of antidepressant drugs. Since L-17 also possesses neuro- and cardioprotective properties, it can be useful in affective illness developing due to the general medical condition, such as post-stroke and post-myocardial infarction (MI) depression.

The limited information available on the structure of complexes involving transcription factors and cognate DNA response elements represents a major obstacle in the quest to understand their mechanism of action at the molecular level. We implemented a concerted structural proteomics approach, which combined hydrogen-deuterium exchange (HDX), quantitative protein-protein and protein-nucleic acid cross-linking (XL), and homology analysis, to model the structure of the complex between the full-length DNA binding domain (DBD) of FOXO4 and its DNA binding element (DBE). The results confirmed that FOXO4-DBD assumes the characteristic forkhead topology shared by these types of transcription factors, but its binding mode differs significantly from those of other members of the family. The results showed that the binding interaction stabilized regions that were rather flexible and disordered in the unbound form. Surprisingly, the conformational effects were not limited only to the interface between bound components but extended also to distal regions that may be essential to recruiting additional factors to the transcription machinery. In addition to providing valuable new insights into the binding mechanism, this project provided an excellent evaluation of the merits of structural proteomics approaches in the investigation of systems that arematerial not directly amenable to traditional high-resolution techniques.

The affinity constant, also known as the equilibrium constant, binding constant, equilibrium association constant, or the reciprocal value, the equilibrium dissociation constant (K_d), can be considered as one of the most important characteristics for any antibody-antigen pair. Many methods based on different technologies have been proposed and used to determine this value. However, since a very large number of publications and commercial datasheets do not include this information, significant obstacles in performing such measurements seem to exist. In other cases where such data are reported, the results have often proved to be unreliable. This situation may indicate that most of the technologies available today require a high level of expertise that does not seem to be available in many laboratories. In this paper, we present a simple approach based on standard immunoassay technology that is easy and quick to perform. It relies on the effect that the molar IC₅₀ approaches the K_d value in the case of infinitely small concentrations of the reagent concentrations. A two-dimensional dilution of the reagents leads to an asymptotic convergence to K_d. The approach has some similarity to the well-known checkerboard titration used for the optimization of immunoassays. A well-known antibody against the FLAG peptide, clone M2, was used as a model system and the results were compared with other methods. This approach could be used in any case where a competitive assay is available or can be developed. The determination of an affinity constant should belong to the crucial parameters in any quality control of antibody-related products and assays and should be mandatory in papers using immunochemical protocols.

One of the most prevalent and deadly types of cancer is breast cancer. The value and effectiveness of the current pharmacological therapy are, however, constrained. Using computational methods and publicly available data, the current study set out to identify the genes and molecular pathways linked to breast cancer. It also looked into potential treatments for the disease that would target these molecular processes. In this study, we mined genes that were strongly associated with breast cancer using text mining and GeneCodis. Using STRING and Cytoscape, protein-protein interaction (PPI) study was carried out. Candidate medications were then derived based on the drug-gene interaction study of the final genes. 2,658 genes linked to breast cancer were found by our investigation using text mining searches. Out of which 166 genes have been taken which are relevant to breast cancer. Ten genes representing ten pathways—which a total of ten proteins could target—were found by gene enrichment analysis. We have taken Holy Basil as our lead as it contains various bioactive compounds such as flavonoids, terpenoids, and phenolics, which have shown antioxidant, anti-inflammatory, and anticancer properties. For this analysis we choose the molecular docking technique to check the effects of different chemical constituents of Holy Tulsi on breast cancer targeted protein and compare their results. We’ve performed the molecular docking in between chemical constituents of Holy Basil and the targeted proteins and determined the binding affinity with the help of PyRx and BIOVIA Discovery studio software. Anti-mitotic activity of Pisum sativum using tulsi extract to check the cytotoxicity effect was done. To determine the toxicity level of the extract on rat liver was performed in the end. In conclusion, investigating candidate medications that target the genes/pathways relevant to breast cancer in order to uncover possible treatments may be accomplished through drug discovery employing in silico text mining and pathway analysis technologies along with the wet lab experimentation with plants and preclinicals.

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.

Long-span steel structure trusses are widely used in factory buildings, but with the growth of service time and the increase of dynamic load fatigue, a considerable part of the long-span truss with dynamic load appears serious transverse cracks at the bottom of the middle span and oblique deformation of the abdomen in the operation process. The U-shaped cracks at the bottom and belly, as well as the mid-span down deflection of the main truss, reduced the functional function of the factory building truss structure, and had to limit the original crane load, which affected the normal safety and durability of the structure. Therefore, the application principle of the variable axial force cable system in the long-span factory building truss structure and 3D3S software modeling [1] were used. Analyzing and studying the reinforcement method of large-span powerhouse truss can provide practical experience for subsequent similar projects. In view of the above phenomenon, the large-span powerhouse trusses of Hongcheng Powerhouse 1 and No.2 located in Tonglu, Zhejiang Province are used as the research object, and the variable axial force cable method is proposed to strengthen and lift the load. Considering the span of large-span powerhouse truss, the cable system with 22m controlling force of 400kN is proposed to be selected for powerhouse 1, and the cable system with variable axial force of 24m is proposed to be selected for Powerhouse 2. The force model of large-span truss is established by using the finite element method commonly used to analyze the force of truss. Under two working conditions, The influence of reinforcement effect is analyzed and compared from three aspects: stiffness, bearing capacity and stability. And the phenomenon of uneven stress distribution is analyzed. The stress distribution characteristics of each node are understood by simulating the most disadvantageous node plates with the greatest internal force before and after reinforcement.

This study delves into the intricate interplay between cosmology and gravity in dilaton-based models, enhancing our understanding. Exploring boundary theories coupled to gravity, we derive a four-dimensional effective theory from the cosmological constant. Dilaton gravity is then scrutinized, revealing elegant solutions and insights into brane embedding. The analysis extends to probe scalar fields, employing the WKB approximation in both conformal and non-conformal cases. In summary, this work contributes to a nuanced understanding of the complex relationship between cosmology and gravity in dilaton-based frameworks.

We introduce the linear subgroup of volume-preserving diffeomorphism as the underlying symmetry to construct an action within the effective field theory framework and the Schwinger-Keldish formalism. The formulated action is posited to effectively incorporate dissipative effects into the Navier-Stokes equations.