Identification of fulvestrant analogues for estrogen receptor alpha binding in breast cancer using molecular docking and molecular dynamics simulation

Breast cancer remains a major global health challenge, with approximately 80% of cases classified as estrogen receptor-positive (ER+). Fulvestrant, a steroidal antiestrogen and selective estrogen receptor degrader (SERD), is widely used in ER+ breast cancer therapy; however, its clinical efficacy is limited by low bioavailability and resistance. In this study, we employed a computational approach to evaluate Fulvestrant analogues for their predicted interaction with the estrogen receptor alpha (ERα). Molecular docking identified three analogues (9BETA,11ALPHA,13ALPHA,14BETA,17ALPHA)-11-(METHOXYMETHYL) ESTRA-1(10),2,4-TRIENE-3,17-DIOL [EED], 2-Hydroxyestradiol, and Ethinylestradiol with more favorable binding energy (BE) values than Fulvestrant. Molecular dynamics (MD) simulations suggested that 2-Hydroxyestradiol maintains computationally stable and compact ERα complexes comparable to Fulvestrant, supported by hydrogen-bond analyses. Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) predictions indicated that Fulvestrant maintained the most favorable safety profile despite pharmacokinetic limitations, while 2-Hydroxyestradiol displayed more predictable metabolism but raised concerns of hepatotoxicity and carcinogenicity. EED and Ethinylestradiol were further constrained by significant toxicity risks. Overall, the computational evidence highlights 2-Hydroxyestradiol as a theoretically promising scaffold for further structural optimization rather than as a direct therapeutic candidate. These exclusive in-silico findings provide predictive insights for prioritizing Fulvestrant analogues; however, experimental validation through in vitro ERα binding, cytotoxicity assays in ER+ breast cancer cell lines, followed by in vivo studies is essential to assess clinical relevance.