Screening of the Antagonistic Activity of Potential Bisphenol A Alternatives toward the Androgen Receptor Using Machine Learning and Molecular Dynamics Simulation

Over the past few decades, extensive research has indicated that exposure to bisphenol A (BPA) increases the health risks in humans. Toxicological studies have demonstrated that BPA can bind to the androgen receptor (AR), resulting in endocrine-disrupting effects. In recent investigations, many alternatives to BPA have been detected in various environmental media as major pollutants. However, related experimental evaluations of BPA alternatives have not been systematically implemented for the assessment of chemical safety and the effects of structural characteristics on the antagonistic activity of the AR. To promote the green development of BPA alternatives, high-throughput toxicological screening is fundamental for prioritizing chemical tests. Therefore, we proposed a hybrid deep learning architecture that combines molecular descriptors and molecular graphs to predict AR antagonistic activity. Compared to previous models, this hybrid architecture can extract substantial chemical information from various molecular representations to improve the model's generalization ability for BPA alternatives. Our predictions suggest that lignin-derivable bisguaiacols, as alternatives to BPA, are likely to be nonantagonist for AR compared to bisphenol analogues. Additionally, molecular dynamics (MD) simulations identified the dihydrotestosterone-bound pocket, rather than the surface, as the major binding site of bisphenol analogues. The conformational changes of key helix H12 from an agonistic to an antagonistic conformation can be evaluated qualitatively by accelerated MD simulations to explain the underlying mechanism. Overall, our computational study is helpful for toxicological screening of BPA alternatives and the design of environmentally friendly BPA alternatives.