Machine Learning-Based Quantitative Structure-Activity Relationship and ADMET Prediction Models for ERα Activity of Anti-Breast Cancer Drug Candidates

Abstract

Breast cancer is presently one of the most common malignancies worldwide, with a higher fatality rate. In this study, a quantitative structure-activity relationship (QSAR) model of compound biological activity and ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) properties prediction model were performed using estrogen receptor alpha (ERα) antagonist information collected from compound samples. We first utilized grey relation analysis (GRA) in conjunction with the random forest (RF) algorithm to identify the top 20 molecular descriptor variables that have the greatest influence on biological activity, and then we used Spearman correlation analysis to identify 16 independent variables. Second, a QSAR model of the compound were developed based on BP neural network (BPNN), genetic algorithm optimized BP neural network (GA-BPNN), and support vector regression (SVR). The BPNN, the SVR, and the logistic regression (LR) models were then used to identify and predict the ADMET properties of substances, with the prediction impacts of each model compared and assessed. The results reveal that a SVR model was used in QSAR quantitative prediction, and in the classification prediction of ADMET properties: the SVR model predicts the Caco-2 and hERG(human Ether-a-go-go Related Gene) properties, the LR model predicts the cytochrome P450 enzyme 3A4 subtype (CYP3A4) and Micronucleus (MN) properties, and the BPNN model predicts the Human Oral Bioavailability (HOB) properties. Finally, information entropy theory is used to validate the rationality of variable screening, and sensitivity analysis of the model demonstrates that the constructed model has high accuracy and stability, which can be used as a reference for screening probable active compounds and drug discovery.