The effect of genotype variation and M423 resistance mutations to the binding of phosphonomidate-based inhibitor IDX17119 with the thumb-II domain of Hepatitis C virus RdRp: an integrated molecular dynamics and binding free energy study

Abstract

ABSTRACT The IDX17119 is a phosphonomidate-based pan-genotypic non-nucleoside inhibitor of Hepatitis C Virus (HCV) NS5B RdRp thumb-II domain. IDX17119 exhibits significant antiviral activity against HCV genotype (GT) 1a, 2a, 3a and 4a. The molecular docking analysis was performed to understand the binding and intermolecular interactions of the IDX17119 molecule at the thumb-II domain of 1a, 2a, 3a and 4a GT NS5B RdRps. The molecular dynamics simulation has been performed to determine the stability of the ligand–protein complexes. We found GT 1a complex is relatively stable compared with other drug-receptor complexes. The binding free energy calculations and free energy decomposition analysis were carried out for all the complexes, the result revealed that the increase in the unfavourable polar contribution affects the binding of IDX17119 with GT 2a NS5B RdRp compared with all other complexes. In addition to this, the effect of mutation at M423 site (M423T/V) alters the conformation and activity of the IDX17119 molecule.