Pharmacophore-guided identification of flavonoid compounds as potential inhibitors for 3C protease of enterovirus A71 and coxsackievirus A16

Hand, Foot, and Mouth Disease (HFMD), caused primarily by Enteroviruses A71 (EV-A71) and Coxsackievirus A16 (CV-A16), poses a significant public health concern, particularly in children. The 3C protease (3Cpro) enzymes of these viruses are attractive drug targets for potential antiviral therapies. This study employed computational techniques to identify potential inhibitors for the 3Cpro of EV-A71 and CV-A16. Utilizing rupintrivir as a reference, we developed pharmacophore models and screened a flavonoid database, resulting in the selection of diosmin, epigallocatechin gallate (EGCG), and RTH-011 as promising candidates. Molecular docking studies revealed favorable binding interactions for diosmin and EGCG, suggesting their potential as inhibitors. Experimental validation demonstrated the non-toxic nature of diosmin and EGCG to human Rhabdomyosarcoma (RD) cells and their antiviral activity against EV-A71 and CV-A16. These findings highlight the potential of diosmin and EGCG as promising antiviral agents for HFMD, warranting further drug development efforts.