title: Analysis of the Resistance of Hepatitis C Virus NS5B Polymerase Inhibitors via Docking and Molecular Dynamics Simulation.
abstract: In this work, we examined how known single point mutations (P495S, P495L, P495A, P496A, P496S and V499A) in Hepatitis C virus NS5B polymerase influence the binding of benzimidazole-5-carboxamide derivatives which are potent NS5B inhibitors. Docking and molecular dynamics simulations were performed to analyze the binding of the inhibitors to the wild-type and mutant enzymes. Binding free energy calculations (MM-GB/SA method) and analyzing the decomposed binding free energy of individual residues were able to explain the differences in the inhibitory potency of the compounds at wild-type and mutant enzymes and hence account for the appearance of resistance of mutant enzymes to the studied inhibitors. The obtained results were found to be in agreement with the known experimental data.
authors.affiliation: Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany phone: +49-345-55-25040; fax: +49-345-55-27355.
authors.forename: Tanaporn
authors.initials: T
authors.lastname: Uengwetwanit
authors.affiliation: Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany phone: +49-345-55-25040; fax: +49-345-55-27355.
authors.forename: Dina
authors.initials: D
authors.lastname: Robaa
authors.affiliation: Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany phone: +49-345-55-25040; fax: +49-345-55-27355. wolfgang.sippl@pharmazie.uni-halle.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D009154:Mutation; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Binding free energy; Hepatitis; MM-GB/SA; Mutation; NS5B polymerase