Structure-based In-silico Screening Reveals Promising Repurposed Drugs for Targeting Monkeypox Virus Proteins

Background: Monkeypox (mpox) has re-emerged as a significant global health concern, with outbreaks prompting public health emergencies. Despite the availability of vaccines and a few non-specific antivirals, no targeted therapy has been approved for pox, underscoring the urgent need for novel treatment strategies. Objectives: This study aimed to identify potential high-affinity drug candidates against mpox by repurposing existing compounds using structure-based molecular docking. It focused on five essential viral proteins involved in the virus’s replication and pathogenesis. Methods: Five mpox viral proteins—A48R (thymidylate kinase), A50R (DNA ligase), D13L (capsid protein), F13L (envelope protein), and I7L (cysteine protease)—were modeled using AlphaFold2 and prepared using Chimera and PyRx software. Over 300 compounds with known antiviral activity were screened using molecular docking with AutoDock Vina. The binding energies and protein-ligand interactions were analyzed using PyMOL and Discovery Studio. Top candidates were selected based on binding affinity, pharmacokinetics, and safety profiles. Results: Several repurposed drugs demonstrated superior binding affinities compared to known inhibitors. Notably, baicalin (-10.0 kcal/mol) for A48R, ledipasvir (-10.3 kcal/mol) for A50R and I7L, and suramin (-13.2 and -10.7 kcal/mol) for D13L and F13L outperformed reference compounds. These drugs also exhibited favorable pharmacokinetic properties and established safety profiles. Conclusion: This in silico drug repurposing approach highlights promising candidates for further investigation of mpox. The findings offer a foundation for experimental validation and support accelerated therapeutic development for emerging poxvirus threats.