PreprintArticleVersion 1This version is not peer-reviewed
Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3/4A Serine Protease
Version 1
: Received: 13 July 2024 / Approved: 14 July 2024 / Online: 16 July 2024 (04:54:08 CEST)
How to cite:
Iman, K.; Mirza, M. U.; Sadia, F.; Froeyen, M.; Trant, J. F.; Chaudhary, S. U. Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3/4A Serine Protease. Preprints2024, 2024071116. https://doi.org/10.20944/preprints202407.1116.v1
Iman, K.; Mirza, M. U.; Sadia, F.; Froeyen, M.; Trant, J. F.; Chaudhary, S. U. Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3/4A Serine Protease. Preprints 2024, 2024071116. https://doi.org/10.20944/preprints202407.1116.v1
Iman, K.; Mirza, M. U.; Sadia, F.; Froeyen, M.; Trant, J. F.; Chaudhary, S. U. Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3/4A Serine Protease. Preprints2024, 2024071116. https://doi.org/10.20944/preprints202407.1116.v1
APA Style
Iman, K., Mirza, M. U., Sadia, F., Froeyen, M., Trant, J. F., & Chaudhary, S. U. (2024). Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3/4A Serine Protease. Preprints. https://doi.org/10.20944/preprints202407.1116.v1
Chicago/Turabian Style
Iman, K., John F. Trant and Safee Ullah Chaudhary. 2024 "Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3/4A Serine Protease" Preprints. https://doi.org/10.20944/preprints202407.1116.v1
Abstract
The emergence of drug resistance inducing mutations in Hepatitis C virus (HCV) coupled with genotypic heterogeneity has made targeting NS3/4A serine protease difficult. In this work, we investigated the mutagenic variations in the binding pocket of Genotype 3 (G3) HCV NS3/4A and evaluated ligands for efficacious inhibition. We report mutations at 14 positions within the ligand-binding residues of HCV NS3/4A including H57R and S139P within the catalytic triad. We then modeled each mutational variant for pharmacophore-based virtual screening (PBVS) followed by covalent docking towards identifying a potential covalent inhibitor, i.e. cpd-217. The binding stability of cpd-217 was then supported by molecular dynamic simulation followed by MM/GBSA binding free energy calculation. The free energy decomposition analysis indicated that the resistant mutants alter the HCV NS3/4A-ligand interaction, resulting in an unbalanced energy distribution within the binding site leading to drug resistance. cpd-217 was identified to interact with all NS3/4A G3 variants with significant covalent docking scores. In conclusion, cpd-217 emerges as a potential inhibitor of HCV NS3/4A G3 variants that warrants further in vitro and in vivo studies. The study will pave the way for drug design and development of HCV G3 NS3/4A.
Keywords
Hepatitis C virus; MD Simulations; Covalent inhibitor; Drug resistance; Pharmacophore-based virtual screening
Subject
Biology and Life Sciences, Life Sciences
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
,
