Through Bioinformatics, Can an Extract from Diospyros montana Offer Broad-Spectrum Inhibition Against EV-A71 2C Protein?

Enterovirus A71 (EV-A71), belonging to the Picornaviridae family, is the primary causative agent of hand, foot, and mouth disease (HFMD) in children under five years of age, and no specific broad-spectrum antiviral therapy is currently available. Despite having extensive research on the EV-A71 3C protease, another nonstructural protein, the 2C protein, which is a highly conserved protein and a member of the ATPases Associated with diverse cellular Activities (AAA+) helicase family, lacks conclusive details of its mechanism. This study, thereby, performed a comprehensive analysis of the wild-type EV-A71 2C protein by studying the role of Zn2+ in structural stability and determining the binding site with two pronounced inhibitors—fluoxetine 12b and dibucaine 6i—as the positive controls via the blind docking method. Then, a virtual screening on a Vietherb database (5071 metabolites from Vietnamese natural sources) yielded 20 top-ranked compounds, which were selected for further molecular dynamics (MD) simulation and cross-variant evaluation. Among these, CID 101282068 extracted from Diospyros montana exhibited overall good, predicted binding affinity (docking score of −9.8 kcal/mol and Gbind = −33.27 kcal/mol) and sustained the highest number of persistent hydrogen bonds with critical residues at the oligomerization interface. Further validation against 23 EV-A71 2C variants highlights its hypothetical broad-spectrum characteristics and can be considered a promising lead candidate targeting EV-A71 2C multimers.