Targeting the catalytic ATP-binding site of Japanese Encephalitis Virus RNA-dependent RNA polymerase using integrated structure-based drug discovery.

Abstract

Despite current advances, Japanese Encephalitis Virus (JEV) still poses a considerable risk because effective antiviral drugs are lacking. The RdRp protein is the main component of viral genome replication and therefore a primary target for antiviral drug development. In this study, we applied a drug discovery protocol with multiple parameters to identify RdRp inhibitors. Using a pharmacophore model, ligand-based screening of the ADMET-like Screening Compound Library, which had more than 448,000 molecules, was carried out, and 102,496 hits were generated. The three-level docking cascade, namely HTVS, SP, and XP, together with an initial MM-GBSA calculation, was used to identify F6548-1309, F0877-0123, and F1683-2814 as candidate inhibitors due to their good binding affinities. Further optimization was done through density functional theory (DFT), and the reactivity and electronic stability of the candidates were studied. Five independent Molecular dynamics (MD) simulations with random velocities were carried out to ensure accuracy and reproducibility. The MD simulations revealed that the candidates were dynamically stable. Furthermore, the PCA and FEL showed the candidates' conformational stability. This indicates that the selected compounds have stronger binding affinity to RdRp than the reference compound CHEMBL464432.