Structural Insights into Plasticity and Discovery of Flavonoid Allosteric Inhibitors of Flavivirus NS2B–NS3 Protease

Flaviviruses are among the most critical pathogens in tropical regions; they cause various severe diseases developing countries but not restricted to these countries. The development of antiviral therapeutics is crucial for managing flavivirus outbreaks. Ten proteins encoded RNA. N2B–NS3pro protein complex plays a fundamental role replication and promising drug target; however, no protease inhibitors have progressed preclinical stage. This study analyzed structural models plasticity NS2B–NS3pro five medically important non-dengue flaviviruses (West Nile, Rocio, Ilhéus, yellow fever, Saint Louis encephalitis). flavonoids amentoflavone, tetrahydrorobustaflavone, quercetin were selected their exceptional binding energies as potential complex. AutoDock Vina results ranged from −7.0 kcal/mol −11.5 compounds preferentially acted non-competitively. Additionally, first model was proposed Ilhéus Rocio viruses. an attractive molecular target development. three identified natural showed great inhibitory against viral species. Nevertheless, further silico vitro studies required obtain more information regarding inhibition by therapeutic potential.