Filibuvir(FBV)is presently one of the most advanced non-nucleoside inhibitors(NNIs)of the hepatitis C virus(HCV)NS5B RNA-dependent RNA polymerase(RdRp).In present study,the selectivity mechanism of Filibuvir toward wild-type(WT)and mutant NS5B polymerases(including V494I,V494A,M426A and M423T)was investigated by molecular modeling methods.The predicted binding free energies of these five complexes are strictly consistent with experimental data and can give a good explanation of the differences in curative efficacy of Filibuvir.The analysis of the individual energy terms indicates that the van der Waals interaction is crucial to distinguish the binding affinities of these five systems.Moreover,we compare RdRpV494I/FBV,RdRpWT/FBV,RdRpV494AI/FBV and RdRpV494G/FBV complexes and find that the longer side chains of residue 494 the shallower binding pocket of the systems and then the more favorable for Filibuvir binding to NS5B RdRps.The poor efficacy of Filibuvir toward RdRpM426A is mainly due to the decrease of interaction between Filibuvir and residue Leu-497M426A caused by the spatial structure change of Ala-426M426A.The mutation M423T influences the curative efficacy of Filibuvir by making the binding pocket small and shallow,which leads to the cyclopentyl group exposing outside the pocket then decreases the binding affinity.In a word,the molecular dynamics is successfully employed to interpret the selectivity mechanism of Filibuvir,and our work will provide valuable information for developing more potent and selective inhibitors toward HCV NS5B polymerase.