Molecular Screening and Free Energy Calculations‐Based Exploration of Medicinal Phytocompounds Chemical Space to Abrogate G9R‐E4R Complex from Monkeypox: A Current Global Health Threat

Abstract The current monkeypox virus outbreak is probably linked with the novel substitutions in the G9R protein of the replication complex. The G9R‐E4R interface act as a potential druggable site for the inhibition of monkeypox replication. Therefore, we employed computational methods to explore potential natural products to inhibit the G9R interface. Our results revealed that among the 5230 compounds only four compounds (top hit 1‐4) reported excellent docking scores of ‐8.96 kcal/mole, ‐8.33 kcal/mol, ‐7.98 kcal/mol and ‐7.85 kcal/mol respectively. However, the reported KD value were ‐7.68 kcal/mol, ‐7.05 kcal/mol, ‐7.53 kcal/mol, and ‐7.77 kcal/mol respectively. The selected lead compounds exhibited consistent dynamics in all‐atoms simulations, reflects their robustness and suitability for engaging effectively with the interface residues. Furthermore, the binding free energy was calculated to be ‐47.86 kcal/mol for the top hit 1 complex, ‐45.51 kcal/mol for the top hit 2 complex, ‐41.63 kcal/mol for the top hit 3 complex, and ‐43.81 kcal/mol for the top hit 4 complex. These compounds also showed favorable pharmacokinetic properties with minimal toxicity risks. The results indicate that compounds top hit 1‐4 demonstrate a higher pharmacological potential against the G9R protein of monkypox virus, suggesting immediate experimental testing to assess their clinical viability.