Computational screening of bacterial and fungal natural compounds targeting monkeypox virus DNA polymerase (F8) holoenzyme

The Orthopoxvirus known as the monkeypox virus (MPXV) has resurfaced as a global public health concern and is becoming increasingly difficult to control due to growing resistance to tecovirimat and the limitations of current antiviral treatments. This study focused on natural product-based inhibitors targeting the viral DNA polymerase holoenzyme (PDB ID: 8HG1), an essential replication complex mechanistically distinct from conventional therapies. A comprehensive computer-aided drug design workflow was used to screen 36,395 natural compounds through molecular docking, followed by pharmacokinetic and toxicity evaluation. This initial phase identified CIDs: 14378518, 135779135, and 101904856 as lead candidates with high binding free energies of -10.221, -10.055, and -10.054 kcal/mol, along with favourable pharmacokinetic and safety profiles. Further validation using MM-GBSA, QM calculations, and SAR analysis supported their binding potential and antiviral relevance. To thoroughly evaluate the stability and binding integrity of these complexes, 100 ns molecular dynamics (MD) simulations were conducted, analysing metrics including RMSD, RMSF, Rg, SASA, hydrogen bond, protein-ligand contact analyses, PCA, and DCCM. Overall, CIDs: 14378518 (Juglomycin C) from Streptomyces sp. strain 815 and 135779135 (Lamellicolic anhydride) from Coniothyrium cereale demonstrated optimal stability, compactness, and sustained protein-ligand interactions during simulation. Juglomycin C showed the most favourable binding energy profile observed in both post-docking (-5.44 kcal/mol) and post-simulation analyses (-26.30 to -27.24 kcal/mol), whereas Lamellicolic anhydride exhibited the best overall simulation stability, outperforming all evaluated compounds across the majority of dynamic parameters. Thus, these findings emphasize their potential as promising natural product-derived candidates for future experimental validation in MPXV antiviral research.