title: Computational study on the molecular mechanisms of drug resistance of Narlaprevir due to V36M, R155K, V36M+R155K, T54A, and A156T mutations of HCV NS3/4A protease.
abstract: Narlaprevir is a novel NS3/4A protease inhibitor of hepatitis C virus (HCV), and it has been tested in a phase II clinical trial recently. However, distinct drug-resistance of Narlaprevir has been discovered. In our study, the molecular mechanisms of drug-resistance of Narlaprevir due to the mutations V36M, R155K, V36M+R155K, T54A, and A156T of NS3/4A protease have been investigated by molecular dynamics (MD) simulations, free energy calculations, and free energy decomposition analysis. The predicted binding free energies of Narlaprevir towards the wild-type and five mutants show that the mutations V36M, R155K, and T54A lead to low-level drug resistance and the mutations V36M+R155K and A156T lead to high-level drug resistance, which is consistent with the experimental data. The analysis of the individual energy terms indicates that the van der Waals contribution is important for distinguishing the binding affinities of these six complexes. These findings again show that the combination of different molecular modeling techniques is an efficient way to interpret the molecular mechanism of drug-resistance. Our work mainly elaborates the molecular mechanism of drug-resistance of Narlaprevir and further provides valuable information for developing novel, safer, and more potent HCV antiviral drugs in the near future.
authors.affiliation: School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Yuquan Road 19A, 100049 Beijing, P.R. China.
authors.forename: Huiqun
authors.initials: H
authors.lastname: Wang
authors.forename: Lingling
authors.initials: L
authors.lastname: Geng
authors.forename: Bo-Zhen
authors.initials: BZ
authors.lastname: Chen
authors.forename: Mingjuan
authors.initials: M
authors.lastname: Ji
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D003521:Cyclopropanes; D004151:Dipeptides / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000235:genetics; D005814:Genes, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics*; D007930:Leucine / Q000031:analogs & derivatives; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011392:Proline / Q000031:analogs & derivatives; D013450:Sulfones / Q000494:pharmacology*; D014508:Urea; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D004151:Dipeptides; D007930:Leucine; D011392:Proline; D013450:Sulfones; D014508:Urea; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C552043:narlaprevir
keywords: Narlaprevir; drug-resistance; molecular dynamics (MD) simulations; molecular mechanism; mutation; mécanisme moléculaire; narlaprévir; résistance médicamenteuse; simulations de dynamique moléculaire (DM)