Prediction of drug-binding sites in HCV NS5B polymerase: MD simulation study

Hepatitis C virus (HCV) is a small, single-stranded, positive-sense ribonucleic acid (RNA) virus and is a member of the Flaviviridae family of viruses. Its genome has a length of 9.6 kb and encoding a polyprotein of about 3000 amino acids which is cleaved co- and post-translationally by cellular and viral proteases into 10 different products: core, envelope protein E1, E2, p7, nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B. Core, E1 and E2 are the main viral constituents of the HCV particle. NS5B of the hepatitis C virus, a RNA-dependent RNA polymerase, is an important therapeutic target. In order to gain deeper insight into and to know its molecular mechanism, the authors employed molecular dynamics simulation at the nanosecond scale. Initial coordinates were taken from the protein data bank entries with IDs 3IGV and 3GYN. The present study shows the strong binding affinity of the inhibitor with NS5B polymerase. The binding free energies, calculated by the molecular mechanics and Poisson–Boltzmann surface area/generalized Born surface area method, suggest a good connection with the experimental biological activity. The analysis of the combined simulation results has identified that Tyr448, Ser556 and Asp318 are the key amino acid residues in NS5B binding. The results obtained from this study provide some insights into the development of novel strong NS5B inhibitors.