Academic Journal
Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3/4A Serine Protease
| Title: | Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3/4A Serine Protease |
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| Authors: | Kanzal Iman, Muhammad Usman Mirza, Fazila Sadia, Matheus Froeyen, John F. Trant, Safee Ullah Chaudhary |
| Source: | Viruses, Vol 16, Iss 8, p 1250 (2024) |
| Publisher Information: | MDPI AG, 2024. |
| Publication Year: | 2024 |
| Collection: | LCC:Microbiology |
| Subject Terms: | Hepatitis C virus, MD simulations, covalent inhibitor, drug resistance, pharmacophore-based virtual screening, Microbiology, QR1-502 |
| More Details: | 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 modelled 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 unbalanced energy distribution within the binding site, leading to drug resistance. Cpd-217 was identified as interacting 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. This study provides a theoretical foundation for drug design and development targeting HCV G3 NS3/4A. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 16081250 1999-4915 |
| Relation: | https://www.mdpi.com/1999-4915/16/8/1250; https://doaj.org/toc/1999-4915 |
| DOI: | 10.3390/v16081250 |
| Access URL: | https://doaj.org/article/5012ef92da2b40af9dddc0f0eba8f9f7 |
| Accession Number: | edsdoj.5012ef92da2b40af9dddc0f0eba8f9f7 |
| Database: | Directory of Open Access Journals |
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| ISSN: | 16081250 19994915 |
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| DOI: | 10.3390/v16081250 |
| Published in: | Viruses |
| Language: | English |