Phytoestrogen-mediated modulation of estrogen receptors: elucidating the binding interactions and pharmacokinetic profiles in breast cancer treatment

Introduction: Estrogen receptor(ER) signalingiscentral to the pathogenesisand therapeutictargeting ofbreast cancer. ER signaling is modulated differentially by its subtypes, with ER-alpha promoting cell growth and ER-beta acting as a suppressor. Estradiol is the dominant endogenous estrogen before menopause, whereas estrone predominates post-menopause, further complicating hormonal dynamics in breast tissue. Objective: To investigate the binding af fi nities and selectivity of 15 phytoestrogen molecules to ER-alpha and ER-beta receptorsincomparisontoendogenousestrogens(estradiolandestrone)andtoevaluatetheirdruglikenessfororalab-sorption using Lipinski's Rule of Five. Methods: Molecular docking analysis was performed to assess the binding interactions between the selected phytoestrogens, ER-alpha, ER-beta, estradiol, and estrone. Lipinski's Rule of Five was applied to determine the phytoestrogens' suitability for oral administration. Results: Genistein, Daidzein, and Glycitein demonstrated strong and preferential binding to ER-beta compared to ER-alpha. The remaining phytoestrogens analyzed displayed greater af fi nity for ER-alpha. All phytoestrogens were evaluatedfordruglikeness,with themajoritymeetingLipinski'sRuleofFivecriteria,suggestingfavorableoralabsorp-tion potential. Conclusions: TheselectivebindingofGenistein, Daidzein, and GlyciteintoER-beta highlightstheir possibleanti-tumor effects andpositionsthemaspromisingcandidatesforfurtherbiological and pharmacological evaluation with respect to ER-beta-mediated breast cancer therapy. Distinct interactions of phytoestrogens with ER isoforms underscore the importance of receptor subtype targeting in breast cancer research and therapy development.