Structure Prediction and Potential Inhibitors Docking of Enterovirus 2C Proteins

Human enterovirus infections are mostly asymptomatic and occasionally could be severe and life-threatening. The conserved non-structural 2C from enteroviruses protein is a promising target in antiviral therapies against human enteroviruses. Understanding of 2C-drug interactions is crucial for developing the potential antiviral agents. While functions of enterovirus 2C proteins have been widely studied, three-dimensional structure information of 2C is limited. In this study, the structures of 2C proteins from 20 enteroviruses were simulated and reconstructed using programs. Subsequent docking studies of the known 22 antiviral inhibitors for 2C proteins were performed to uncover the inhibitor-binding characteristics of 2C. Among the potential inhibitors, the compound hydantoin exhibited the highest broad-spectrum antiviral activities with binding to 2C protein. The anti-enteroviral activity of GuaHCL, compound 19b, R523062, compound 12a, compound 12b, quinoline analogs 12a, compound 19d, N-benzyladenosine, dibucaine derivatives 6i, TBZE-029, fluoxetine analogs 2b, dibucaine, 2-(α-hydroxybenzyl)-benzimidazole (HBB), metrifudil, pirlindole, MRL-1237, quinoline analogs 10a, zuclopenthixol, fluoxetine, fluoxetine HCl, and quinoline analogs 12c showed a trend of gradual decrease. In addition, the free energy with 22 compounds binding to EV 2C ranged from -0.35 to -88.18 kcal/mol. Our studies will provide important information for the development of pan-enterovirus antiviral agents based on 2C.