Probing the origin of estrogen receptor alpha inhibition via large-scale QSAR study

Abstract

Estrogen is an important component for the sustenance of normal physiological functions of the mammary glands, particularly for growth and differentiation. Approximately, two-thirds of breast cancers are positive for estrogen receptor (ERs), which is a predisposing factor for the growth of breast cancer cells. As such, ERα represents a lucrative therapeutic target for breast cancer that has attracted wide interest in the search for inhibitory agents. However, the conventional laboratory processes are cost- and time-consuming. Thus, it is highly desirable to develop alternative methods such as quantitative structure–activity relationship (QSAR) models for predicting ER-mediated endocrine agitation as to simplify their prioritization for future screening. In this study, we compiled and curated a large, non-redundant data set of 1231 compounds with ERα inhibitory activity (pIC₅₀). Using comprehensive validation tests, it was clearly observed that the model utilizing the substructure count as descriptors, performed well considering two objectives: using less descriptors for model development and achieving high predictive performance (R_Tr² = 0.94, Q_CV² = 0.73, and Q_Ext² = 0.73). It is anticipated that our proposed QSAR model may become a useful high-throughput tool for identifying novel inhibitors against ERα.