Inhibition of the viral RNA-dependent RNA polymerase (RdRp) to resolve chronic infection is a useful therapeutic strategy against Hepatitis C virus (HCV). Non-nucleoside inhibitors (NNIs) of RdRp are small molecules that bind tightly with allosteric sites on the enzyme, thereby inhibiting polymerase activity. A large number of crystal structures (176) were studied to establish the structure-activity relationship along with the mechanism of inhibition and resistance between HCV RdRp and NNIs at different allosteric sites. The structure and the associated dynamics are the blueprint to understand the function of the protein. We have implemented the ligand-based pharmacophore and molecular dynamic simulations to extract the possible local and global characteristics of RdRp upon NNI binding and the structural-dynamical features possessed by the known actives. Our results suggest that the NNI binding induces significant fluctuations at the atomic level which are critical for enzymatic activity, with minimal global structural alterations. Residue-wise mapping of interactions of NNIs at different sites exhibited some conserved interaction patterns of key amino acids and water molecules. Here, the structural insights are explored to understand the correlation between the dynamics of protein's subdomains and function at the molecular level, useful for genotype-specific rational designing of NNIs.Communicated by Ramaswamy H. Sarma.
Keywords: Allosteric sites; genotypes; ligand-based pharmacophore; molecular dynamics (MD) simulation; mutations; non-nucleoside inhibitors (NNIs).