Mechanistic insights into the Japanese Encephalitis Virus RNA dependent RNA polymerase protein inhibition by bioflavonoids from Azadirachta indica

Abstract

Japanese encephalitis (JE) virus, belongs to the genus flavivirus, is a major cause of viral encephalitis, which results in neurological damage. RNA-dependent RNA polymerase (RdRp) protein is the sole enzyme responsible for viral genome replication in RNA viruses and serves as an excellent target for anti-viral therapeutic development, as its homolog is not present in humans. In this study, the crystal structure of JE RNA-dependent RNA polymerase (jRdRp) protein was obtained from protein data bank while 43 by bioflavonoids reported in Azadirachta indica were retrieved from the PubChem database. Following, structure based virtual screening was employed using MTiOpenScreen server and top four compounds, viz. Gedunin, Nimbolide, Ohchinin acetate, and Kulactone, with the most negative docking scores (> -10 kcal/mol) conformations were redocked using AutoDock Vina; these complexes showed mechanistic interactions with Arg474, Gly605, Asp668, and Trp800 residues in the active site of jRdRp protein against reference ligand, i.e., Guanosine-5'-Triphosphate. Furthermore, 100 ns classical molecular dynamics simulation and binding free energy calculation showed considerable stability (via hydrogen bonding and hydrophobic interactions) of docked bioflavonoids in the active pocket of jRdRp and significant contribution of van der Waals interactions for docked complex stability during simulation, respectively. Therefore, the outcome of this study predicted the substantial anti-viral activity of Gedunin, Nimbolide, Ohchinin acetate, and Kulactone against jRdRp protein and can be considered for further antiviral drug development.

Antiviral drug research for Japanese encephalitis: an updated review

“…AutoDock Vina [138,140,146] Novel ligands developed with v1.2 software NS3 protein 43 bioactive bioflavonoids reported in Azadirachta indica RdRp protein modeler 9.10 [132] Mycophenolate E-protein GOLD Suite 5.1 [142] Compounds screened from the ZINC database NS3 helicase/nucleoside GLIDE [147] Phytoconstituents of the Arisaema JEV NS3 helicase, NS2B-NS3 protease, and NS5 Molegro Virtual Docker (MVD) [121] Atropine and scopolamine NS3 protein iGEMDOCKv2.1 [148] Aminoglycoside and Tetracycline group of compounds NS3 helicase / nucleoside tripeptide NSK [154], griffithsin [112], and other drug candidates [105,107].…”