Abstract
Selective estrogen receptor modulators (SERMs) play a vital role in ER + ve breast cancer therapy, but existing synthetic drugs have limitations. This study explores Pyrenacantha volubilis as a potential natural source for SERM using molecular docking, ADMET profiling, molecular dynamics (MD) simulations, and MM-GBSA analysis, using the Schrödinger Suite. Nine metabolites reported from the species were subjected to analysis, and all except one exhibited superior activity compared to the control. Among these, pumiloside (- 13.06 kcal/mol), strictosidine (- 11.808 kcal/mol), deoxypumiloside (- 11.686 kcal/mol), and strictosamide (- 11.479 kcal/mol) demonstrated stronger ERα binding affinities than control drugs tamoxifen and raloxifene. The receptor-ligand complexes of pumiloside and strictosidine exhibited reasonable interactions, with strictosidine showing the highest glide energy (- 52.418 kcal/mol). MD simulations and MM-GBSA analysis further confirmed the stability of these complexes under physiological conditions, with both compounds showing superior free binding energy compared to tamoxifen. Deoxypumiloside also emerged as a promising candidate with no Lipinski rule of five violations and high oral absorption, but required solubility enhancements. Additionally, 10-hydroxy camptothecin, protonated strictosidine, camptothecin, 9-methoxy camptothecin, 20-deoxy camptothecin, and 20-hexanoyl-10-methoxy camptothecin are other metabolites that exhibited good docking scores and favorable drug-like properties. These findings highlight P. volubilis as a promising SERM source, with strictosidine and pumiloside as lead candidates due to their superior receptor interactions, stability, and energetics. Further in vitro and in vivo studies are required to validate their therapeutic potential in breast cancer treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04315-4.