Molecular Image-Based Prediction Models of Nuclear Receptor Agonists and Antagonists Using the DeepSnap-Deep Learning Approach with the Tox21 10K Library

The interaction of nuclear receptors (NRs) with chemical compounds can cause dysregulation of endocrine signaling pathways, leading to adverse health outcomes due to the disruption of natural hormones. Thus, identifying possible ligands of NRs is a crucial task for understanding the adverse outcome pathway (AOP) for human toxicity as well as the development of novel drugs. However, the experimental assessment of novel ligands remains expensive and time-consuming. Therefore, an in silico approach with a wide range of applications instead of experimental examination is highly desirable. The recently developed novel molecular image-based deep learning (DL) method, DeepSnap-DL, can produce multiple snapshots from three-dimensional (3D) chemical structures and has achieved high performance in the prediction of chemicals for toxicological evaluation. In this study, we used DeepSnap-DL to construct prediction models of 35 agonist and antagonist allosteric modulators of NRs for chemicals derived from the Tox21 10K library. We demonstrate the high performance of DeepSnap-DL in constructing prediction models. These findings may aid in interpreting the key molecular events of toxicity and support the development of new fields of machine learning to identify environmental chemicals with the potential to interact with NR signaling pathways.