Computational interrogation of natural compounds identified resveratrol-3-O-D-glucopyranoside as a potential inhibitor of essential monkeypox virus proteins

Monkeypox has become a significant public health concern owing to the recent epidemics and associated morbidity. The treatment is limited by the availability of drugs, especially in endemic communities. Computational methods can facilitate the discovery and development of new and effective therapies that are affordable. This study was aimed at identifying potential drug candidates from the SuperNatural chemical library against monkeypox virus essential proteins using computational methods. We identified 7 highly conserved essential proteins involved in monkeypox virus (MPXV) replication, infectivity, and propagation as potential therapeutic targets. A library of 447 orally administrable drug-like compounds from the SuperNatural database was screened against the proteins for potential binders/ligands associations using virtual screening and molecular dynamics simulations. Our search identified hit compounds that mimicked the tecovirimat binding pose and outperformed it in binding affinity. Notably, resveratrol-3-O-D-glucopyranoside showed significant binding affinity to the viral protein F13L, a key protein involved in MPXV transmission. Extensive molecular dynamics simulations showed stable interactions between resveratrol-3-O-β-D-glucopyranoside and F13L, and other hit compounds with their respective targets. Although the predicted interactions require further experimental validation, our results suggested that the identified compounds could be promising therapeutic candidates for the development of novel monkeypox drugs. These findings might underscore the significance of natural compounds in drug discovery and lay the foundation for developing novel antivirals against monkeypox.