Computational investigation of tomatidine and gedunin as probable inhibitors of mpox virus proteins

• The reemergence of mpox highlights the urgent need for new and effective antiviral treatments. • key compounds gedunin and tomatidine showed strong mpox target proteins binding. • A 300ns MD simulation showed the stable binding of gedunin and tomatidine to mpox target proteins. • PCA and gmxMMPBSA validated the MD results, thus supporting the potential efficacy of the phytoligands. • This study paves the way for natural compounds as therapies against mpox and other viruses. The reemergence of monkeypox (mpox) poses an increasing global health threat to human health, highlighting the pressing need for effective treatments. The lack of approved antivirals for mpox treatment highlights the need for targeted protein-specific therapeutic inhibitors. This study examined two mpox proteins, DNA polymerase holoenzyme (DPH) and profilin-like protein (PLP)— as promising therapeutic targets. A library of phytochemicals were subjected to systematic computational screening to assess their interactions with these viral proteins. Screening analysis revealed that gedunin exhibited strong binding affinity toward DPH, achieving a docking score of -10.9 kcal/mol. Tomatidine followed closely with a score of -10.7 kcal/mol. Both compounds interacted with the active sites of the target proteins. Similarly, two candidates for PLP were stylopine and friedelin, with docking scores of -10.5 and -10.4 kcal/mol, respectively. The chosen compounds, tomatidine and gedunin, exhibited negative Ames toxicity, satisfied key safety benchmarks, and conformed to Lipinski’s rule of drug-likeness. These compounds underwent 300 ns molecular dynamics simulations (MDS), followed by Principal Component Analysis (PCA) and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. The ΔG binding values determined by MM/PBSA for the tomatidine-DPH, tomatidine-PLP, gedunin-DPH, and gedunin-PLP interactions were measured at -20.39±2.11, -23.44±5.81, -24.97±2.92, and -7.23 ±2.27 kcal/mol, respectively. Additionally, key residues involved in stabilizing ligand binding within the active pockets were identified. Overall, the findings suggest that these phytochemicals hold significant potential as novel therapeutic candidates against the mpox virus. The outcomes of this investigation provide a solid foundation for exploring plant-based molecules as promising antiviral candidates for a range of severely infectious viruses.