Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure-based virtual screening

摘要: Hand, foot and mouth disease (HFMD) is a serious, highly contagious disease. HFMD caused by Enterovirus 71 (EV71), results in severe complications even death. The pivotal role of EV71 3Cpro the viral life cycle makes it an attractive target for drug discovery development to treat HFMD. In this study, we identified novel inhibitors docking-based virtual screening. Totally 50 compounds were selected test their inhibitory activity against 3Cpro. best inhibitor DC07090 exhibited inhibition potency with IC50 value 21.72 ± 0.95 μM without apparent toxicity (CC50 > 200 μM). To explore structure-activity relationship DC07090, 15 new derivatives designed, synthesized evaluated in vitro enzyme assay accordingly. Interestingly, four showed activities only inhibited replication EC50 22.09 ± 1.07 μM. Enzyme kinetic experiments that compound was reversible competitive inhibitor. Ki determined be 23.29 ± 12.08 μM. Further molecular docking, MD simulation mutagenesis studies confirmed binding mode Besides, could also inhibit coxsackievirus A16 (CVA16) 27.76 ± 0.88 μM. Therefore, represents non-peptidyl small molecule further antiviral therapy or other picornaviruses.