Mechanistic insights into the Japanese encephalitis virus RNA dependent RNA polymerase protein inhibition by bioflavonoids from Azadirachta indica

Dwivedi, Vivek Dhar; Singh, Ankita; El-Kafraway, Sherif Aly; Alandijany, Thamir A.; Faizo, Arwa A.; Bajrai, Leena Hussein; Kamal, Mohammad Amjad; Azhar, Esam Ibraheem

Japanese encephalitis (JE) virus is a flavivirus causing encephalitis causing neurological damage. RNA-dependent-RNA-polymerase (RdRp) is responsible for genome replication making it excellent anti-viral target. In this study, the crystal structure of JE RdRp (jRdRp) and bioflavonoids reported in Azadirachta indica were retrieved from specific databases. Structure-based virtual screening was employed using MTiOpenScreen server and top four compounds selected with the most negative docking scores. Conformations were redocked using AutoDock Vina; these complexes showed mechanistic interactions with Arg(474), Gly(605), Asp(668), and Trp(800) residues in the active site of jRdRp, i.e., guanosine-5′-triphosphate. Furthermore, 100 ns classical molecular dynamics simulation and binding free energy calculation showed stability of docked bioflavonoids in the active jRdRp pocket and significant contribution of van-der-Waals interactions for docked complex stability during simulation. Therefore, this study predicted the anti-viral activity of Gedunin, Nimbolide, Ohchinin acetate, and Kulactone against jRdRp and can be considered for further antiviral drug development.