Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: Cell culture and molecular docking study

Parvez, Mohammad K.; Tabish Rehman, Md.; Alam, Perwez; Al-Dosari, Mohammed S.; Alqasoumi, Saleh I.; Alajmi, Mohammed F.

During the past decades, antiviral drug research technology has helped establish many efficacious anti-HBV drugs that eventually lead to emergence of drug-resistant strains. Hence, new antiviral strategies must focus not only on synthetic molecules but also on potential natural or plant products. Antiviral drug discovery and development passes through several stages, of which the in vitro cell culture systems and in silico molecular modeling represent first and fastest drug screening steps. Absence of a robust cell culture system for the propagation of HBV impeded the in vitro antiviral studies until the advent of HBV DNA cloning and establishment of stable cell lines. The HBV-reporter cell line, HepG2.2.15 is one of the established systems for preliminary screening of anti-HBV drugs. In the present study, the anti-HBV potential of specifically selected natural compounds was assessed by their inhibitory effects on HBsAg and HBeAg expressions in the HepG2.2.15 culture supernatants. Of these, quercetin, psoralen, baccatin III, menisdaurin, embelin and azadirachtin showed the high activities whereas lupeol, rutin, b-sitosterol and hesperidin had moderate efficacies against HBV replication. HBV Pol is the most important viral protein as potential drug-target despite emergence of drug-resistant mutations in and around the Pol/RT 'YMDD' motif (Locarnini et al., 2008) . We used homology modeling to generate a 3-D structure of HBV Pol and validated it by Ramachandran plot wherein the 'YMDD' corresponded to the Tyr203, Met204, Asp205 and Asp206 residues. To further delineate the binding mechanism of the anti-HBV active compounds and lamivudine (ligands) to the modeled HBV Pol (receptor), we performed molecular docking. Docking of lamivudine indicated that it strongly interacted with the active site of HBV Pol through bonding with Pro59, Ala181, Ser202 and Ala181, forming a stable lamivudine-Pol complex with an estimated Gibb's free energy of À5.2 kcal/mol. Interestingly therein, the two Pol 'YMDD' motif residues, Tyr203 and Met204 were among the lamivudine surrounding amino acids.