157 Available online at www.medicinescience.org ORIGINAL ARTICLE Medicine Science 2021;10:157-61 Computational binding analysis and toxicity evaluation of estrogen receptor with estradiol and the approved SERMs raloxifene, tamoxifen, and toremifene Esma Eryilmaz Dogan Department of Biomedical Engineering, Faculty of Technology, Selcuk University, Konya, Turkey Received 11 August 2020; Accepted 02 December 2020 Available online 20.01.2021 with doi: 10.5455/medscience.2020.08.161 Copyright@Author(s) - Available online at www.medicinescience.org Content of this journal is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Abstract Estrogen receptor is a key feature of many complex disorders. Natural estrogen ligand, estradiol has been investigated in the pharmaceutical aspect of breast cancer, Parkinson’s, Alzheimer’s, risk of stroke in postmenopausal women, and dementia. From the similar manner, synthetic selective estrogen receptor modulators (SERMs) have been investigated, and their pharmaceutical efects have been evaluated in compared to the natural ligand, estradiol, in literature. To design better alternatives to the approved SERMs and to improve the clinical observations, it is crucial to understand the molecular basis of drug-target interactions of estrogen receptor with the natural and synthetic ligands in a comparative manner. We used molecular modeling softwares PyRX, Avogadro, and Arguslab for in silico calculations. The results were analyzed using PyMol. We, in this study, provided a computational binding analysis of the estrogen receptor with the endogenous ligand estradiol and the FDA approved SERMs raloxifene, tamoxifen, and toremifene. We investigated the toxicity profle of the SERMs and estradiol and interpreted the results according to the reported clinical obser- vations. We found that designing new molecules based on the estradiol structure instead of the approved tamoxifen analogs could result in better clinical observations for future estrogen targeting therapeutics. Keywords: Estrogen receptor; estradiol; in silico; tamoxifen; raloxifene; molecular docking; toxicity Introduction Breast cancer, described by uncontrolled growth of epithelial cells in breast is the second most common type of cancer in women. It is also seen rare cases in men. Over time, breast cancer has been classifed based on the mechanism and the pathways of carcinoma, and these classifcations have resulted in the fundamental targets for prognosis and treatment of the disease. Hormonal targets such as progesterone, androgen, and especially estrogen receptors (ER) constitute an important group of molecular targets as the hormone- receptor positive breast cancer constitutes two cases out of three diagnosis according to the American Cancer Society [1]. Estrogen receptor is actively used in today’s diagnosis of breast cancer and the treatment has been based on the level of estrogen receptor found in the body. Estradiol, the natural and endogenous ligand, also known as E2 is a hormone binding the estrogen receptor, circulating within the human body, and acting as a main female sex hormone. Estradiol plays important roles in many biological process such as regulating ERα levels in hypothalamic neurons [2], signaling for estrogen dependent behavior [3], and protecting hippocampal neurons [4]. Its neuroprotective efect has also been clearly established from animal studies [5, 6]. Binding of estradiol with ER gives insight regarding binding energy, binding pocket, and other binding related parameters. Therefore, we used estradiol for investigating the binding dynamics of ER and comparing the results with the FDA approved synthetic ligands, raloxifene, tamoxifen, and toremifene, called selective estrogen receptor modulators (SERMs). Binding of estrogen receptor with a bioactive small molecule has been manipulated to control the functionality of estrogen with synthetic ligands. For that, tamoxifen has been approved by FDA in 1977 to treat ER+ breast cancer upon with the proven benefts of the molecule in clinic. However, later studies have shown that patients treated with tamoxifen have been found developing an *Coresponding Author: Esma Eryilmaz Dogan, Department of Biomedical Engineering, Faculty of Technology, Selcuk University, Konya, Turkey E-mail: eeryilmaz@selcuk.edu.tr Medicine Science International Medical Journal