Repurposing of FDA-Approved Antiviral Drugs against Monkey Pox Virus: A Computational Targeting of VP39 Methyl transferase

The recent resurgence of Monkeypox virus (MPXV), a zoonotic orthopoxvirus, has led to a significant increase in global cases, highlighting the urgent need for effective antiviral therapies. Drawing parallels with previous outbreaks such as SARS-CoV-2, where drug repurposing played a crucial role in accelerating treatment development, the present study employs a computational approach to identify potential antiviral agents against MPXV. The viral protein VP39, a 2′-O-methyltransferase responsible for mRNA capping, is critical to MPXV replication and immune system evasion. Its absence in humans and essential enzymatic role make it an attractive target for drug intervention. In this study, 25 FDA-approved antiviral drugs were screened against the sinefungin-binding pocket of VP39 using structure-based molecular docking, molecular dynamics (MD) simulations, and MM-GBSA binding energy analysis. Among them, Adefovir emerged as the most promising candidate, with a Glide docking score of –8.717 and a binding free energy of –42.25 kcal/mol. Docking interaction analysis revealed strong hydrogen bonding and ionic interactions with key catalytic residues Arg140, Asp138, and Arg143. A 100 ns MD simulation confirmed the complex’s structural stability, supported by consistent RMSD values, low RMSF, a compact radius of gyration, persistent hydrogen-bond interactions. Other compounds like Sofosbuvir, Ribavirin, Zanamivir, and Remdesivir also showed favourable binding profiles, supporting the druggability of the VP39 active site. The consistent binding poses of the top compounds further reinforce VP39’s potential as a drug target. Overall, the findings propose Adefovir as a repurposed candidate present a rapid, cost-effective framework for antiviral discovery.