A Unified Deep Graph Model for Identifying the Molecular Categories of Ligands Targeting Nuclear Receptors

To fulfill functions for differentially regulating the downstream signaling pathways, functional ligands (i.e., agonists or antagonists) targeting nuclear receptors (NRs) are designed to stabilize different conformations (active or inactive) of the proteins. However, in practical applications, it is usually difficult to determine the molecular category of an NR ligand because these molecules all bind in the same location of an NR protein, namely, the ligand-binding pocket (LBP). Considering that ligands with different properties (agonists or antagonists) prefer to bind with differential conformations of NRs, it is possible to identify the molecular type of a given ligand through the differential binding environment (active or inactive conformations) of the protein-ligand interaction. Therefore, in this study, we established a unified model (NRIGN) based on the deep graphic architecture to discriminate agonists and antagonists targeting 26 successful or in-clinical-trial NR targets. Our result shows that NRIGN achieves an excellent prediction accuracy (ACC >0.95) and is robust enough to be applied in various real-world scenarios, such as predicting the molecular type of ligands in crystallized NR structures, ligands with multiple NR activities, and ligands with their types altered by target mutations. The proposed model is expected to promote rational design of drugs targeting NR proteins.