## 1 Introduction  
Breast cancer is the second most common cancer worldwide, with 11.6% of all cancer cases (or 2.3 million new cases) in 2022, and the fourth leading cause of cancer-related mortality, with 6.9% of all cancer deaths (666,000 deaths). By 2040, breast cancer is projected to increase by over 40% [1; 2; 3]. One treatment option for breast cancer involves chemotherapy that specifically targets estrogen receptor alpha (ER\(\alpha\)). ER\(\alpha\) is a nuclear hormone receptor that acts as a ligand-dependent transcription factor. ER\(\alpha\) mediates the effects of estrogen by regulating gene transcription involved in cell proliferation and survival, making it a central target for endocrine therapy in breast cancer [4; 5; 6]. Overexpression or aberrant activation of ER\(\alpha\) is closely associated with tumor progression and poor prognosis in breast cancer patients [7; 8; 9]. Structurally, the ligand-binding domain (LBD) of ER\(\alpha\) is composed of 12 \(\alpha\)-helices that form a large, flexible hydrophobic pocket accommodating a variety of ligands [10]. Key residues within the binding pocket play crucial roles in ligand recognition and binding affinity. The most critical residues identified include Glu353 (helix 3), Arg394 (helix 5), and His524 (helix 11), which form hydrogen bonds with the hydroxyl groups of ligands [11]. An example of an ER\(\alpha\) competitive inhibitor is 4-hydroxytamoxifen (4-OHT). In this compound, the phenolic hydroxyl group interacts with Glu353 and Arg394, while the side chain containing dimethylaminoethoxy lies close to Asp351 and forms a direct hydrogen bond. The large side chain extends from the binding pocket between helices 3 and 11, preventing the hydrophobic interactions between helices 12 and 3/11, thereby helix 12 attains an inactive or open conformation positioned directly opposite helices 3 and 5, occupying the co-regulator binding site [12]. Several selective estrogen receptor modulators (SERMs) have been developed to target ER\(\alpha\), including tamoxifen (and its metabolite 4-OHT), raloxifene, and lasofoxifene (Figure 1) [13]. Tamoxifen is the first-generation SERM widely used for the treatment and prevention of ER\(\alpha\)-positive breast cancer. It acts as an estrogen antagonist in breast tissue, blocking estrogen receptor activation and inhibiting cancer cell growth. Its primary active metabolite, 4-hydroxytamoxifen, binds to ER\(\alpha\) with much higher affinity than tamoxifen and exerts stronger antiestrogenic effects, further preventing estrogen-driven tumor progression [14; 15; 16]. Raloxifene is a second-generation SERM that binds to estrogen receptors, acting as an antagonist in breast and uterine tissues and as an agonist in bone. It is used to reduce the risk of breast cancer in postmenopausal women and to treat osteoporosis. Compared to tamoxifen, raloxifene has less estrogen-like effects on the uterus, resulting in a lower risk of endometrial cancer [17]. Lasofoxifene is a newer SERM that functions similarly by antagonizing ER\(\alpha\) in breast tissue. It is effective in inhibiting tumor growth, including in models resistant to other endocrine therapies, and demonstrates tissue selectivity with beneficial effects on bone and vaginal tissues while having minimal impact on the uterus [18]. However, prolonged use of tamoxifen, raloxifene, and lasofoxifene can cause serious side effects. Tamoxifen increases the risk of endometrial cancer, blood clots, stroke, liver toxicity, and cataracts, as well as persistent hot flashes, menstrual issues, and vaginal discharge. Raloxifene and lasofoxifene also raise the risk of blood clots, with raloxifene potentially increasing stroke risk, especially in women with heart disease. Lasofoxifene may cause benign endometrial changes but does not significantly raise endometrial cancer risk [19; 20; 21; 22].