Structural and computational analysis of monkeypox virus methyltransferase: dynamic inhibition mechanisms and their implications for antiviral design.

Monkeypox (Mpox), an emerging global health threat, necessitates the development of effective antiviral agents. In our study, we selected the Mpox virus methyltransferase VP39 (MTase) protein due to its role in viral replication and immune evasion. The MTase protein is essential in Mpox and is associated with similar replication mechanisms in other viruses like COVID-19, making it a broad-spectrum target for antiviral therapy. We screened the ZINC20 in-stock compounds against the MTase protein, utilizing molecular docking, accompanied by pharmacokinetic analysis to assess their binding affinity and drug-like properties, and conducted molecular dynamic simulations to observe the stability and conformational changes of the protein-ligand complexes over time. The docking results revealed that the highest binding energy was exhibited by ZINC257233856, with a value of - 7.68 kcal/mol, indicating a strong interaction with the MTase protein followed by the other compounds. All the compounds selected for the study showed consistently acceptable safety profiles. Molecular dynamics simulations demonstrated that the selected compounds, specifically ZINC257233856, showed significant stability within the MTase binding pocket. Additionally, solvation thermodynamics were investigated using Grid Inhomogeneous Solvation Theory (GIST), revealing key hydration patterns and thermodynamic hotspots that further support the binding stability of top-ranked inhibitors. Thus, our study demonstrates the promising potential of selected compounds as therapeutic options against Mpox. Our findings lay a foundational basis for further clinical investigation and the development of effective treatments.