Inhibition of Monkeypox Virus DNA Polymerase Using Phytochemicals: Computational Studies of Drug-Likeness, Molecular Docking, Molecular Dynamics Simulation and Density Functional Theory.

The emergence of zoonotic monkeypox (MPX) disease, caused by the double-stranded DNA monkeypox virus (MPXV), has become a global threat. Due to unavailability of a specific small molecule drug for MPX, this study investigated phytochemicals to find potent and safe inhibitors of DNA Polymerase (DNA Pol), a poxvirus drug target due to its role in the viral life cycle. For that, 146 phytochemicals were screened through drug-likeness and molecular docking analyses. Among these, 136 compounds exhibited drug-like properties, with Gossypetin showing the highest binding affinity (- 7.8 kcal/mol), followed by Riboflavin (- 7.6 kcal/mol) and Ellagic acid (- 7.6 kcal/mol). In comparison, the control drugs Cidofovir and Brincidofovir displayed lower binding affinities, with binding energies of - 6.0 kcal/mol and - 5.1 kcal/mol, respectively. Hydrogen bonds, electrostatic and hydrophobic interactions were the main non-bond interactions between inhibitors and protein active site. The identified compounds were further evaluated using molecular dynamics simulation, density functional theory analysis and ADMET analysis. Molecular dynamics simulations conducted over 200 ns revealed that DNA Pol-Gossypetin complex was not stable, however, Riboflavin and Ellagic acid complexes showed excellent stability indicating them as better DNA Pol inhibitors. The density functional theory analysis exhibited the chemical reactivity of these inhibitor compounds. The ADMET analysis suggested that the top phytochemicals were safe and showed no toxicity. In conclusion, this study has identified Riboflavin and Ellagic acid as potential DNA Pol inhibitors to control MPXV. Further experimental assays and clinical trials are needed to confirm their activity against the disease.