title: Molecular principles behind Boceprevir resistance due to mutations in hepatitis C NS3/4A protease.
abstract: The hepatitis C virus (HCV) infection is a primary cause of chronic hepatitis which eventually progresses to cirrhosis and in some instances might advance to hepatocellular carcinoma. According to the WHO report, HCV infects 130-150 million people globally and every year 350,000 to 500,000 people die from hepatitis C virus infection. Great achievement has been made in viral treatment evolution, after the development of HCV NS3/4A protease inhibitor (Boceprevir). However, efficacy of Boceprevir is compromised by the emergence of drug resistant variants. The molecular principle behind drug resistance of the protease mutants such as (V36M, T54S and R155K) is still poorly understood. Therefore in this study, we employed a series of computational strategies to analyze the binding of antiviral drug, Boceprevir to HCV NS3/4A protease mutants. Our results clearly demonstrate that the point mutations (V36M, T54S and R155K) in protease are associated with lowering of its binding affinity with Boceprevir. Exhaustive analysis of the simulated Boceprevir-bound wild and mutant complexes revealed variations in hydrophobic interactions, hydrogen bond occupancy and salt bridge interactions. Also, substrate envelope analysis scrutinized that the studied mutations reside outside the substrate envelope which may affect the Boceprevir affinity towards HCV protease but not the protease enzymatic activity. Furthermore, structural analyses of the binding site volume and flexibility show impairment in flexibility and stability of the binding site residues in mutant structures. In order to combat Boceprevir resistance, renovation of binding interactions between the drug and protease may be valuable. The structural insight from this study reveals the mechanism of the Boceprevir resistance and the results can be valuable for the design of new PIs with improved efficiency.
authors.affiliation: Department of Biotechnology, Delhi Technological University, Delhi 110042, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Nagpal
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan 304022, India.
authors.forename: Sukriti
authors.initials: S
authors.lastname: Goyal
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Divya
authors.initials: D
authors.lastname: Wahi
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Ritu
authors.initials: R
authors.lastname: Jain
authors.affiliation: Department of Bioscience and Biotechnology, Banasthali University, Tonk, Rajasthan 304022, India.
authors.forename: Salma
authors.initials: S
authors.lastname: Jamal
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Aditi
authors.initials: A
authors.lastname: Singh
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Preeti
authors.initials: P
authors.lastname: Rana
authors.affiliation: School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India. Electronic address: abhinavgr@gmail.com.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Grover
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D011392:Proline; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide
keywords: Boceprevir; HCV; Molecular dynamics; Mutants; Resistance; Simulations