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Exploring Antiviral Chemical Space for the Discovery of Novel RNA-Dependent RNA Polymerase inhibitors against Japanese Encephalitis Virus

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Author Affiliations

  • 1Department of Biological Sciences, Faculty of Science and Environment, Mahatma Gandhi Chitrakoot Gramodaya Vishwavidyalaya, Chitrakoot, Satna, India
  • 2Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
  • 3Bioinformatics Research Division, Quanta Calculus, Greater Noida, UP, India
  • 4Department of Biological Sciences, Faculty of Science and Environment, Mahatma Gandhi Chitrakoot Gramodaya Vishwavidyalaya, Chitrakoot, Satna, India

Int. Res. J. Biological Sci., Volume 15, Issue (3), Pages 15-27, August,10 (2026)

Abstract

This research focuses on Japanese encephalitis virus (JEV), one of the most serious mosquito-borne flaviviruses that cause neuroinvasive disease in humans. Despite the wide use of vaccines, there is still a high burden of JEV infections for which there are no good therapies. One of the main enzymes responsible for viral replication is the RNA-dependent RNA polymerase (RdRp), and it could be a good drug target. Thus, in the current research, we employed a structure-based virtual screening strategy to predict inhibitors of the JEV RdRp enzyme using the enzyme's crystal structure and Life Chemicals' antiviral library. Fifteen candidates were identified during the screening process and then re-scored using MM/GBSA calculations. After scoring using MM/GBSA values, the three top-ranking molecules (F3217-0045, F1951-0385, and F1951-0396), together with the reference inhibitor Galidesivir, underwent detailed analysis via molecular dynamics simulations. All three selected molecules interacted stably with the catalytically active sites in the ATP-binding pocket and exhibited higher binding affinity than the reference inhibitor. The trajectory analysis and trajectory-based MM/GBSA calculations indicated that all three selected compounds formed stable protein-ligand complexes over 100 ns of MD. Particularly, F3217-0045 had the best binding free energy (-84.95 ± 5.71 kcal/mol) among the three molecules, and F1951-0396 had the highest stability during the molecular dynamics simulation. Overall, the results presented constitute the discovery of promising lead molecules that inhibit JEV-RdRp and provide a basis for further experimental studies.

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