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

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 (pIC(50)). 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(Tr)(2) = 0.94, Q(CV)(2) = 0.73, and Q(Ext)(2) = 0.73). It is anticipated that our proposed QSAR model may become a useful high-throughput tool for identifying novel inhibitors against ERα.