Identifying potential compounds from Bacopa monnieri (brahmi) against coxsackievirus A16 RdRp targeting HFM disease (tomato flu)

Hand, foot, and mouth disease (HFMD), primarily instigated by Coxsackievirus A16 (CVA16), poses a serious health concern, necessitating effective therapeutic interventions. The RNA-dependent RNA polymerase (RdRp) of CVA16 emerges as a promising drug target for HFMD treatment. This study presents an in-silico pipeline for the identification of potential RdRp inhibitors against CVA16. A library of 91 natural compounds derived from Bacopa monnieri (brahmi) was virtually screened against the CVA16 RdRp. Here, Bacobitacin D emerged as a promising hit molecule, forming 8 hydrogen bonds including key catalytic site residues (Asp²³⁸ and Asp³²⁹) within the RdRp active site. Further, molecular dynamics (MD) simulations and MM/GBSA binding free energy calculations was applied on the top three hits that were selected based on exhaustive docking scores (≤−9.55 ​kcal/mol). Bacobitacin D exhibited sustainable stability, as evidenced by minimal deviation (RMSD ​= ​0.75 ​± ​0.02 ​nm) during a 100 ns MD simulation. Importantly, Bacopaside IV exhibited the lowest ΔG_TOTAL binding free energy (−23.70 ​kcal/mol), while Bacobitacin D displayed a comparable ΔG_TOTAL of −19.14 ​kcal/mol. Structural interpretation of the most populated cluster derived from MD simulations showed direct interactions of Bacobitacin D with pivotal catalytic residues, including Asp²³⁸ and Ser²⁸⁹. This comprehensive study confirmed Bacobitacin D as a potent inhibitor of CVA16 RdRp, offering a potential avenue for therapeutic intervention against HFMD. Experimental validation is required to confirm the inhibitory action of Bacobitacin D against HFMD.