Discovery of Terpenes as Novel HCV NS5B Polymerase Inhibitors via Molecular Docking

Hepatitis C virus (HCV) is a dangerous virus that is responsible for a large number of infections and deaths worldwide. In the treatment of HCV, it is important that the drugs are effective and do not have additional hepatotoxic effects. The aim of this study was to test the in silico activity of 1893 terpenes against the HCV NS5B polymerase (PDB-ID: 3FQK). Two drugs, sofosbuvir and dasabuvir, were used as controls. The GOLD software (CCDC) and InstaDock were used for docking. By using the results obtained from PLP.Fitness (GOLD), pKi, and binding free energy (InstaDock), nine terpenes were finally selected based on their scores. The drug-likeness properties were calculated using Lipinski's rule of five. The ADMET values were studied using SwissADME and pkCSM servers. Ultimately, it was shown that nine terpenes have better docking results than sofosbuvir and dasabuvir. These were gniditrin, mulberrofuran G, cochlearine A, ingenol dibenzoate, mulberrofuran G, isogemichalcone C, pawhuskin B, 3-cinnamyl-4-oxoretinoic acid, DTXSID501019279, and mezerein. Each docked complex was submitted to 150 ns-long molecular dynamics simulations to ascertain the binding stability. The results show that mulberrofuran G, cochlearine A, and both stereoisomers of pawhuskin B form very stable interactions with the active site region where the reaction product should form and are, therefore, good candidates for use as effective competitive inhibitors. The other compounds identified in the docking screen either afford extremely weak (or even hardly any) binding (such as ingenol dibenzoate, gniditrin, and mezerein) or must first undergo preliminary movements in the active site before attaining their stable binding conformations, in a process which may take from 60 to 80 ns (for DTXSID501019279, 3-cinnamyl-4-oxoretinoic acid or isogemichalcone C).