Prenylated Phytoestrogens as Selective Estrogen Receptor Modulators for Breast Cancer: A Molecular Docking and Dynamics Study

Background: Phytoestrogens share common structural features with human estradiol, which primarily contribute to the proliferation of breast tissue cells by binding Estrogen Receptor (ER) subtypes. The Selective Estrogen Receptor Modulators (SERMs) have many therapeutic implications, including Estrogen Receptor Positive Breast Cancer (ERPBC). Prenylated phytoestrogens have emerged as attractive flavonoid scaffolds for ERβ-selective agonists, with potential for effective utilisation in the development of anti-breast cancer agents. Aim: Exploring prenylated phytoestrogens as selective ERβ agonists for Estrogen Receptor positive breast cancer therapy. Methods: To investigate the SERM modulatory activity of prenyl phytoestrogens, molecular docking, Molecular Mechanics with Generalised Born Surface Area (MM-GBSA) and dynamic simulation approach. Prenylated phytoestrogens were retrieved from pubchem database and screened against ERα and ERβ. The pharmacokinetic parameters like Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) predictions were done to analyse drug likeness, human oral absorption and toxicity. Results: In total, 215 prenylated phytoestrogens were retrieved from pubchem database by similarity searching, and six of them, namely, Gamma Mangostin, GancaoninL, Licocoumarone, 2,3-Dehydrokievitone and Xanthohumol, showed binding towards ERβ with a significant docking score comparable with that of the standard ERβ selective agonist genistein. Molecular dynamics studies indicated the stability of the top-scoring compound Gancaonin L, and the required mode of binding is significant. MM-GBSA implies good affinity of these compounds with ERβ. On in silico ADME prediction using Qikprop, all the compounds showed good human oral absorption, poor blood-brain barrier permeability and less toxicity. Conclusion: The present study highlights that the prenylated phytoestrogens may act as selective ERβ modulators based on their favourable in silico ADME profiles, high affinity, and specific binding mode. Further in vitro and in vivo validation will provide additional insights in developing ERβ modulators into potential anti-breast cancer agents. Major Findings: The top-scoring compounds can serve as fundamental scaffolds for further exploration and development of novel SERMs.