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

Abstract

Abstract 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.