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.

Azadirachtin is the secondary metabolite of Indian neem (Azadirachta indica). In a single report, while the neem leaves extract showed inhibition of dengue virus (DNV) replication, the pure azadirachtin did not reveal any inhibitory effect in vitro and in vivo (Parida et al., 2002) . In this report we demonstrated the novel anti-HBV activity of azadirachtin. Our docking study showed interaction of azadiractin with HBV Pol through Glu1, Pro5, His156, Ser117, Arg120 and Arg153, resulting in a stable azadiractin-Pol complex with a free energy of À8.1 kcal/mol. Though the triterpenoid lupeol has shown weak antiviral activities in several studies, lupeol isolated from Strobilanthes cusia root has demonstrated a robust anti-HSV activity in vitro (Flekhter et al., 2004) . It has therefore, served as a lead drug for the generation of more effective compounds against HSV and Influenza A (Zheng et al., 2009 ). In line with its antiviral activities, we showed the moderate anti-HBV potential of lupeol in vitro. In our in silico analysis, lupeol interacted with HBV Pol through Trp3, Pro5, Leu42 and Arg120, His156 and Tyr158, and stabilized the lupeol-Pol complex with a free energy À8.1 kcal/mol. Rutin, a well-known therapeutic flavonol has been reported for in vitro antiviral activities against avian influenza virus (H5N1) and murine norovirus (MNV) (Carvalho et al., 2013; Ibrahim et al., 2013; Chéron et al., 2015) . Very recently, we have demonstrated the anti-HBV activity of G. senegalensis leaves extract with high content of rutin Alam et al., 2017) . Though moderate, the anti-HBV activity of rutin in the present study strongly supported our previous finding. When subjected to docking, rutin interacted with HBV Pol by forming bonds with Asn33, Asn36, Arg41, Ser81, Asp83 and Asn248 residues where the rutin-pol complex showed a free energy of À9.2 kcal/mol. Notably therein, Asp 205 and Asp206, the 'YMDD' residues were among the rutin surrounding amino acids.