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

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.