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Over 70% of cases express estrogen receptor \u03b1 (ER\u03b1). The activation of ER\u03b1 promotes tumor proliferation and progression. Furthermore, mutations in ER\u03b1 lead to acquired resistance against standard endocrine therapies such as tamoxifen. The induced resistance posed a significant clinical challenge in metastatic breast cancer. In this study, research for identifying novel, naturally derived compounds to inhibit the Y537S\u2010mutated ER\u03b1 was conducted using in silico methods supported by an in\u00a0vitro cytotoxicity screen. Molecular docking and molecular dynamics simulations served as the primary in silico screening strategies. The top 2% of candidates were filtered from a docking screen of the IBS natural library composed of over 15,000 chemicals. From this group, 11 compounds were purchased and tested using a cell\u2010based cytotoxicity assay in MCF\u20107 before advancing to detailed simulations. Five candidates were then advanced to 150\u2009ns MD simulations. A post\u2010MD analysis followed, including MM\u2010PBSA binding free energy calculations and principal component analysis (PCA). The phytochemical ibs\u201004156 was identified as the most promising overall candidate, predicted to maintain consistent stability across both the wild\u2010type and Y537S\u2010mutated ER\u03b1, while ibs\u201018821 demonstrated potent mutant\u2010specific inhibition via an allosteric mechanism involving spatial deviations in distal helices H3 and H11. This result shows that mutated ER\u03b1 can be potentially targeted by bioactive phytochemical scaffolds found through molecular modeling, presenting a potential therapeutic strategy for metastatic breast cancer resistant to therapies such as tamoxifen.<\/jats:p>","DOI":"10.1111\/cbdd.70393","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T05:50:33Z","timestamp":1788501033000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of\n                    <scp>ER<\/scp>\n                    \u03b1\u2010Targeting Phytochemicals With In\u00a0Vitro Cytotoxicity and Computational Prediction of\n                    <scp>Y<\/scp>\n                    537\n                    <scp>S<\/scp>\n                    Mutant 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