In silico Exploration of Aegle Marmelos-Derived Compounds as Potential Inhibitors of NS5 RdRp in Japanese Encephalitis Virus

Introduction: Japanese encephalitis virus (JEV) hijacks the host cell's endoplasmic reticulum (ER) to form assembly and replication complexes during replication, leading to the production of multiple copies of JEV negative-sense and positive-sense RNA strands. The non-structural protein NS5 RNA-dependent RNA polymerase (RdRp) is conserved across all Flavivirus species, and its inhibition can suppress Flavivirus replication. The objective of this study is to evaluate the inhibitory potential of 126 Aegle marmelos-derived compounds on JEV NS5 RdRp using computational methods. Methods: A computational (in silico) approach was employed to assess the binding efficacy and inhibitory effects of Aegle marmelos compounds against the NS5 RdRp of JEV. Molecular docking and virtual screening techniques were used to identify potential inhibitors. Results: The analysis revealed that several compounds, specifically IMPHY015072, IMPHY015047, IMPHY014838, and IMPHY011609, demonstrated significant binding affinity towards NS5 RdRp. These compounds effectively reduced JEV replication in silico, compared to control compounds. Furthermore, the selected compounds may potentially lower IL-1β serum levels and mitigate structural abnormalities in brain tissue. Discussion: The in silico analysis in this study demonstrated the potential of Aegle marmelos-derived compounds to inhibit Japanese encephalitis virus (JEV) replication by targeting the conserved NS5 RNA-dependent RNA polymerase (RdRp). The selected compounds—IMPHY015072, IMPHY015047, IMPHY014838, and IMPHY011609—showed strong binding affinity and effectively reduced JEV replication compared to control compounds. Conclusion: The study suggests that specific Aegle marmelos-derived compounds exhibit promising inhibitory effects against JEV NS5 RdRp and could serve as potential therapeutic candidates to treat JEV infection and reduce associated inflammation and neuronal damage.