Evaluating the Binding Potential and Stability of Drug-like Compounds with the Monkeypox Virus VP39 Protein Using Molecular Dynamics Simulations and Free Energy Analysis.

Monkeypox is a re-emerging viral disease with features of infectiously transmitted zoonoses. It is now considered a public health priority because of its rising incidence and transmission from person to person. Monkeypox virus (MPXV) VP39 protein is identified as an essential protein for replication of the virus, and therefore, it is a potential target for antiviral drugs. This work analyzes the binding affinities and the differential conformational stability of three target compounds and one control compound with the VP39 protein through multiple computational methods. The re-docking analysis revealed that the compounds had high binding affinities towards the target protein; among these compounds, compounds and showed the highest binding energies in the virtual screening, and thus, these were considered as the most active inhibitor candidates. Intermolecular interaction analysis revealed distinct binding mechanisms. While compound had very strong hydrogen bonds and hydrophobic interactions, compound had numerous water-mediated interactions, and compound had only ionic and hydrophobic contacts. In molecular dynamic simulations, compounds and showed that the protein-ligand complexes had a stable conformation, with protein RMSD values around 2 Å for both compounds. In contrast, compound was slightly flexible, and the control compound was more flexible. MM/GBSA analysis again supported these results, which gave the binding free energies that were also supportive for these compounds. Notably, all the selected compounds, especially compounds and , demonstrate high binding affinity. Therefore, these compounds can be further tested as antiviral agents against monkeypox treatment.