Computational identification of potential inhibitors for chikungunya virus nsP2pro

Chikungunya virus remains a crucial global health issue with no approved therapy available. In particular, the viral replication is associated with the non-structural protein 2 protease (nsP2pro). In this study, possible inhibitors for nsP2pro from the National Cancer Institute (NCI) database were screened via computational approaches. Molecular docking simulations were initially predicted top potential ligands. MD simulations were then performed to refine the ligand binding pose. During the equilibrium intervals, the ligands formed rigid contacts with the residues Asn476, Ala511, Tyr512, Tyr544 and Trp549 of nsP2pro. Moreover, five compounds probably prevent the biological activity of nsP2pro by increasing the distance of Cys478-Sγ-Nε-His548 and Ser482-Oγ-Nε-His548 pairs. Furthermore, perturbation simulations finally confirmed that NSC 319990, NSC 80731, NSC 80735, NSC 67436 and NSC 37553 compounds exhibited significantly stronger binding affinity, ranging from -9.70 ± 0.61 to -11.71 ± 1.25 kcal mol^-1, than that of the available inhibitor RA-0002034, ΔG _FEP = - 6.45 ± 0.32 kcal mol^-1. Besides, the strong correlation between ΔG _FEP and Cys478-Sγ-Nε-His548 pair suggests that a stronger binding ligand better inhibits the biological activity of nsP2pro. Overall, these findings suggest that five NCI compounds are highly promising candidates for further experimental validation as novel nsP2pro inhibitors.