Computational Study of Estrogen Receptor-Alpha Antagonist with Three-Dimensional Quantitative Structure-Activity Relationship, Support Vector Regression, and Linear Regression Methods
Human estrogen receptor (ER) isoforms, ERα and ERβ, have long been an important focus in the field of biology. To better understand the structural features associated with the binding of ERα ligands to ERα and modulate their function, several QSAR models, including CoMFA, CoMSIA, SVR, and LR methods, have been employed to predict the inhibitory activity of 68 raloxifene derivatives. In the SVR and LR modeling, 11 descriptors were selected through feature ranking and sequential feature addition/deletion to generate equations to predict the inhibitory activity toward ERα. Among four descriptors that constantly appear in various generated equations, two agree with CoMFA and CoMSIA steric fields and another two can be correlated to a calculated electrostatic potential of ERα. 1. Introduction Estrogens are critical in the physiology of the female reproductive system, the maintenance of bone density, and cardiovascular health [1, 2]. Estrogen receptors are classified into two isoforms, ERα and ERβ, both of which are members of the nuclear receptor superfamily of ligand-modulated transcription factors [3, 4]. When the natural ligand estradiol or other ligands bind to ERα, complex signaling networks lead to a conformational change, specifically in the activation function (AF)-2 helix (H12), allowing estradiol to bind to chromatin; this, in turn, activates or inhibits responsive genes [5, 6]. ERα and ERβ are the targets of pharmaceutical agents used to fight cancers of the reproductive organs, for example, prostate, uterine, and breast cancer [6, 7]. These pharmaceutical agents are divided into three distinct categories: (i) receptor agonists such as 17β-estradiol, the estrogen receptor’s natural ligand; (ii) antiestrogens, such as the compound ICI 164,384 [5, 8]; and (iii) raloxifene (arylbenzothiophene) [5, 9] and tamoxifen [10], both of which act as agonists as well as antagonists. Raloxifene (compound 25 in Table 1) is a selective estrogen receptor modulator (SERM) providing a safer alternative to estrogen because it is an ER antagonist in mammary tissue and the uterus and also mimics the agonist effects of estrogen on bone and in the cardiovascular system [11]. The U.S. Food and Drug Administration (FDA) recently approved raloxifene for the treatment of osteoporosis [12], and it is also being tested as a preventive drug against breast cancer and coronary heart disease [5, 9]. Because drug resistance and serious side effects, such as venous thromboembolism and fatal stroke, have been reported [13], there is a crucial need for new therapeutic agents. Two
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