###### Abstract  
Breast cancer progression is strongly influenced by estrogen receptor-\(\alpha\) (ER\(\alpha\)), a ligand-activated transcription factor that regulates hormone binding, DNA interaction, and transcriptional activation. ER\(\alpha\) plays a key role in promoting cell proliferation in breast tissue, and its overexpression is associated with the advancement of breast cancer through estrogen-mediated signaling pathways. Targeting ER\(\alpha\) is, therefore, a promising therapeutic strategy for breast cancer. However, there are currently no phytochemical-based drug candidates approved for effectively inhibiting breast cancer progression driven by elevated ER\(\alpha\) expression. This study aims to identify phytochemical inhibitors from _Croton bonplandianum_ against ER\(\alpha\) using pharmacokinetics approaches. Eight-three bioactive compounds from _C. bonplandianum_ were retrieved from the IMPPAT (Indian Medicinal Plants, Phytochemistry, and Therapeutics) database and screened through molecular docking for their binding affinity to ER\(\alpha\). The top candidates were further evaluated through molecular dynamics simulations, ADME analysis, toxicity assessment, and quantum mechanics-based DFT calculations. The thermodynamic properties and HOMO-LUMO energy gap values indicated that the selected compounds were both stable and active. Among them, 2,3-oxidosqualene (CID-5366020) and 5,8,11-eicosatryonic acid, trimethylsilyl ester (CID-91696396) demonstrated the most potent inhibitory activity against ER\(\alpha\). These findings suggest that these compounds have significant potential as therapeutic agents for breast cancer treatment by targeting ER\(\alpha\). breast cancer; estrogen receptor-\(\alpha\); _Croton bonplandianum_; molecular docking; ADMET; DFT; molecular dynamics simulation +
Footnote †: journal: Medical Imaging and Biomedicine  
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0000-0002-3333-3333]A. M. A.  
of the most significant health concerns in the modern era [1; 2]. According to the published epidemiological data, the death rates because of this cancer have risen dramatically in the last two decades throughout the world [3]. Breast cancer claimed the lives of nearly 685,000 people globally in 2020, of which 0.5-1% occurred in men. Furthermore, data from the five years prior to 2020 indicated that, as of the end of that year, there were 7.8 million women diagnosed with BC who were still alive. In 2020, more than 2.3 million women had this sort of cancer diagnosis. These statistics demonstrate the disease's mortality rate, which makes it the most prevalent cancer type worldwide [4]. By the year 2050, it is anticipated that there will be 3.2 million new cases of breast cancer diagnosed in women globally each year [5; 6; 7]. This demonstrates the deadly global impact of this cancer on individuals and underscores the critical need for diagnosis and treatment. As of present, there are no specific pharmaceutical interventions available for the disease. The progression in comprehending the disease's pathophysiology has expanded treatment modalities, including surgery, chemotherapy, and adjuvant radiotherapy, aimed at curing the ailment. Nonetheless, a major challenge in treatment remains the development of chemotherapeutic resistance. For example, Anthracyclines, recognized as a cornerstone in treatment, demonstrate significant efficacy in enhancing survival rates. Nevertheless, their utilization is hindered by enduring toxicities such as cardiotoxicity and hematologic malignancies, particularly in elderly patients with breast cancer [8]. Moreover, resistance to Anthracyclines frequently emerges, leaving limited therapeutic alternatives once resistance develops [9]. Patients with estrogen receptor \(\alpha\) (ER\(\alpha\)) positive breast cancer also reflect this type of resistance.