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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\u2013ligand 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.<\/jats:p>","DOI":"10.3390\/v16081250","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T07:37:30Z","timestamp":1722843450000},"page":"1250","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pharmacophore-Assisted Covalent Docking Identifies a Potential Covalent Inhibitor for Drug-Resistant Genotype 3 Variants of Hepatitis C Viral NS3\/4A Serine Protease"],"prefix":"10.3390","volume":"16","author":[{"given":"Kanzal","family":"Iman","sequence":"first","affiliation":[{"name":"Biomedical Informatics & Engineering Research Laboratory, Department of Life Sciences, Lahore University of Management Sciences, Lahore 36000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad Usman","family":"Mirza","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fazila","family":"Sadia","sequence":"additional","affiliation":[{"name":"Biomedical Informatics & Engineering Research Laboratory, Department of Life Sciences, Lahore University of Management Sciences, Lahore 36000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matheus","family":"Froeyen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, Rega Institute for Medical Research, KU Leuven\u2014University of Leuven, B-3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4780-4968","authenticated-orcid":false,"given":"John F.","family":"Trant","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, University of Windsor, Windsor, ON N9B 3P4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3758-6581","authenticated-orcid":false,"given":"Safee Ullah","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"Biomedical Informatics & Engineering Research Laboratory, Department of Life Sciences, Lahore University of Management Sciences, Lahore 36000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,3]]},"reference":[{"key":"ref_1","unstructured":"Lindenbach, B.D., and Rice, C.M. 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