Dual-Target Repurposing Against Chikungunya Virus: Molecular Docking and Dynamics Reveal Bictegravir and Oxacillin as Promising Leads.

Abstract

Chikungunya virus (CHIKV) remains an important re-emerging arboviral threat, yet no specific antiviral therapy is currently available. This study used a structure-based drug-repurposing approach to identify FDA and internationally approved drugs with potential activity against two therapeutically relevant CHIKV targets: nsP2 protease (essential for nonstructural polyprotein processing) and capsid protein (essential for viral nucleocapsid formation). Molecular docking was performed against both proteins, followed by 100-ns molecular dynamics (MD) simulations of the two highest ranked compounds for each target to assess complex stability. Against nsP2 protease, bictegravir showed the most favorable docking score (-9.5 kcal/mol), followed by simeprevir (-9.3 kcal/mol) and glecaprevir (-9.2 kcal/mol). Against the capsid protein, trovafloxacin ranked first (-8.8 kcal/mol), followed by oxacillin (-8.7 kcal/mol) and paritaprevir (-8.6 kcal/mol). For context, the reference cysteine protease inhibitor E-64 and the pocket-validated ligand ethyl 3-aminobenzoate (EAB) were docked under the identical protocol, and they scored -6.1 and -6.0 kcal/mol against nsP2 protease and capsid protein, respectively, both weaker than every top-ranked hit identified in this study. MD simulation showed that the bictegravir-nsP2 complex maintained persistently negative total interaction energy, generally within -50 to -30 kcal/mol, with Rg fluctuating from approximately 20.6 to 21.8 Å and RMSD stabilizing initially at 1.2-1.8 Å before reaching a later plateau of 3.0-3.8 Å. By contrast, the simeprevir-nsP2 complex displayed a less uniform energetic profile. For the capsid target, the oxacillin complex remained comparatively restrained, with Rg largely within 22.4-23.2 Å and RMSD mostly within 1.4-2.0 Å, whereas the trovafloxacin complex showed greater conformational drift, with RMSD rising to nearly 2.8-3.1 Å. These computational findings prioritize bictegravir and oxacillin for further investigation against CHIKV nsP2 protease and capsid protein, respectively. No biological validation was performed; target inhibition and antiviral activity therefore remain unconfirmed and require biochemical and cell-based evaluation.