Computational discovery of natural inhibitors targeting enterovirus D68 3C protease using molecular docking pharmacokinetics and dynamics simulations

Enterovirus D68 (EV-D68) is a significant global health threat, responsible for severe respiratory and neurological complications, with no FDA-approved antiviral treatments currently available. The 3C protease of EV-D68, an essential enzyme involved in viral replication, represents a key target for therapeutic development. In this study, we employed a comprehensive computational approach, including molecular docking, pharmacokinetic predictions, and molecular dynamics simulations, to identify potential natural inhibitors of the EV-D68 3C protease. Screening a library of natural compounds, Withaferin-A (CID: 265,237) and Baicalin (CID: 64,982) emerged as top candidates due to their favorable pharmacokinetic profiles, high binding affinities (-10.7 kcal/mol for Withaferin-A and -9.5 kcal/mol for Baicalin), and interactions with key residues in the protease's active site. The molecular dynamics simulations demonstrated the stability of the protein-ligand complexes, with low root mean square deviation (RMSD) and fluctuation (RMSF) values over a 100-ns trajectory. Free energy calculations further supported the superior binding efficiency of Withaferin-A. These findings suggest that Withaferin-A and Baicalin have significant potential as natural inhibitors of EV-D68 3C protease, offering a promising foundation for future experimental validation and the development of targeted antiviral therapies against EV-D68.