Computational Drug Repurposing Predicts FDA-Approved Drugs as Potential Inhibitors of Chikungunya Virus nsP2 Protease

Chikungunya virus (CHIKV) infection remains a significant global health threat with no approved specific antiviral therapy. The nonstructural protein 2 protease (nsP2pro) is essential for viral replication and represents an attractive target for structure-based drug design. In this study, we employed a computational drug repurposing strategy to predict potential nsP2pro inhibitors from FDA-approved compound libraries. We performed molecular docking screens of 1820 unique compounds against the nsP2pro active site. The eight selected top-scoring compounds had docking scores better than that of the reference inhibitor pantinin-1. Subsequent molecular dynamics (MD) simulations revealed that, except for lomitapide, which dissociated from the pocket, the remaining leads formed dynamically stable complexes and modulated the catalytic environment in a chemotype-dependent manner. Small molecules expanded both the Cys478-His548 and Ser482-His548 distances, consistent with dyad perturbation, whereas GnRH-like peptides preserved a more compact geometry in the modeled noncovalent complexes, pointing to possible nonproductive occupation of the active-site region. Free energy perturbation calculations further provided a relative energetic ranking that supported the MD-derived mechanistic trends and placed six compounds ahead of pantinin-1 within the present data set. Among the small-molecule candidates, venetoclax and lapatinib emerge as computationally prioritized candidates for future biochemical and antiviral evaluation. Overall, this study provides mechanistic insight into noncovalent recognition of CHIKV nsP2pro and a framework for future experimental validation.