At the present time, molecular modeling methods have been proved to be the effective techniques for investigating the drug resistance mechanism of inhibitors. Filibuvir (FBV) is a potent non-nucleoside inhibitor (NNI) developed by Pfizer in 2009 and shows significant promise in phase IIb clinical trial. To elucidate the drug resistance mechanism of FBV, we systemically investigate the interaction between FBV and the wild-type and mutant (V494I, V494A, M426A, and M423T) NS5B RdRps (genotype 1) by using MD simulations, molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) free energy calculations, and molecular mechanics/generalized born surface area (MM/GBSA) free energy decomposition analysis. Based on the calculations, we disclose the drug resistance mechanism of FBV toward the wild-type and mutant NS5B RdRps. The above work was published in the journal 《Antiviral Research》 (http://pubs.acs.org/doi/abs/10.1021%2Facs.energyfuels.5b01476).
Figure. Molecular cartoon of NS5B RdRpWT (in light-blue) (a) and RdRpM426A (in light-pink) (b) with key residues presented as stick. These key residues in NS5B RdRps are colored. The red dashed lines represent the shortest distances between these two residues.