Targeting Mpox with Natural Products: In Silico Discovery of DNA Topoisomerase 1B Inhibitors

Abstract

Mpox remains a public health concern, and the two drugs in clinical use are already limited by resistance or by doserelated toxicity. Viral DNA topoisomerase 1B (Topo 1B) is an alternative target: the enzyme is required for orthopoxvirus replication and shares less than 45 % sequence identity with its human counterpart. No experimental structure of the mpox enzyme has been deposited, so we built a homology model from vaccinia and variola templates (GMQE 0.94; QMEANDisCo 0.86 ± 0.05) and validated it on the SAVES v6.1 portal, where 95.5 % of residues fell in favoured Ramachandran regions and the ERRAT quality factor reached 95.1 %. We then docked 1,353 phytochemicals, curated from 16 Indian medicinal plants in the IMPPAT 2.0 atlas, into the top-ranked pocket with AutoDock Vina 1.2.5 running under PyRx. One hundred and thirteen compounds, 8 % of the library, scored at or below −9.0 kcal/mol and so outperformed the coumarin reference inhibitor novobiocin (−8.8 kcal/mol) redocked under identical settings. Sequential filtering in SwissADME and ADMETlab 3.0 narrowed these to seven compounds that satisfied the Lipinski and Veber rules and carried no predicted hERG, cytochrome P450 or acute-toxicity liability. Five of the seven are withanolides from Withania somnifera. Withasomidienone (IMPHY000630) returned the best score (−10.3 kcal/mol) but is predicted to be poorly soluble, so we advance Withanolide L (IMPHY009438, −10.2 kcal/mol) as the primary lead: it combines comparable affinity with moderate predicted solubility and no Lipinski violations. Its pose is held by hydrogen bonds to Lys167, Tyr136 and Tyr209 together with π-alkyl and van der Waals contacts. These results are computational predictions and now need enzymatic and cellular testing