title: Computational study on the drug resistance mechanism of HCV NS5B RNA-dependent RNA polymerase mutants V494I, V494A, M426A, and M423T to Filibuvir.
abstract: Filibuvir, a potent non-nucleoside inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp), has shown great promise in phase IIb clinical trial. However, drug resistant mutations towards Filibuvir have been identified. In the present study, the drug resistance mechanism of wild-type (WT) and mutant NS5B polymerases (including V494I, V494A, M426A, and M423T) toward Filibuvir was investigated by molecular modeling methods. The predicted binding free energy of these five complexes is highly consistent with the experimental EC50 values of Filibuvir to the wild-type and mutant NS5B RdRps, V494I<WT<V494A<M426A<M423T. Analysis of the individual energy terms indicates that the loss of binding affinity is mainly attributed to the decrease in the van der Waals interaction contribution. Through detailed analysis of the interaction between FBV and RdRp(V494I), RdRp(WT), RdRp(V494A), RdRp(M426A), and RdRp(M423T), several conclusions are made. Firstly, the smaller size of residue 494 side chain results in the smaller binding affinity between FBV and RdRp. Secondly, the poor inhibition capacity of Filibuvir toward RdRp(M426A) is mainly due to the decrease in the van der Walls interaction between Filibuvir and residue Leu-497(M426A) caused by the spatial structure change of Ala-426(M426A). Thirdly, the decrease in the binding affinity in mutation M423T is attributed to the smaller binding cave and the cyclopentyl group of Filibuvir exposing outside the cave. Our computational results will provide valuable information for developing more potent and selective inhibitors toward HCV NS5B polymerase.
authors.affiliation: School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Yuquan Road 19A, 100049 Beijing, PR China.
authors.forename: Huiqun
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Yuquan Road 19A, 100049 Beijing, PR China.
authors.forename: Chenchen
authors.initials: C
authors.lastname: Guo
authors.affiliation: School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Yuquan Road 19A, 100049 Beijing, PR China. Electronic address: bozhenchen@hotmail.com.
authors.forename: Bo-Zhen
authors.initials: BZ
authors.lastname: Chen
authors.affiliation: School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Yuquan Road 19A, 100049 Beijing, PR China.
authors.forename: Mingjuan
authors.initials: M
authors.lastname: Ji
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011753:Pyrones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics* / Q000378:metabolism; D013816:Thermodynamics; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines
chemical_list: D000998:Antiviral Agents; D011753:Pyrones; D012324:RNA-Dependent RNA Polymerase; D014230:Triazoles; C550357:filibuvir; D011743:Pyrimidines
keywords: Drug resistance mechanism; Filibuvir; Molecular dynamics (MD); Mutation; RNA-dependent RNA polymerase