A machine learning model for classifying G-protein-coupled receptors as agonists or antagonists

BACKGROUND: G-protein coupled receptors (GPCRs) sense and transmit extracellular signals into the intracellular machinery by regulating G proteins. GPCR malfunctions are associated with a variety of signaling-related diseases, including cancer and diabetes; at least a third of the marketed drugs target GPCRs. Thus, characterization of their signaling and regulatory mechanisms is crucial for the development of effective drugs. RESULTS: In this study, we developed a machine learning model to identify GPCR agonists and antagonists. We designed two-step prediction models: the first model identified the ligands binding to GPCRs and the second model classified the ligands as agonists or antagonists. Using 990 selected subset features from 5270 molecular descriptors calculated from 4590 ligands deposited in two drug databases, our model classified non-ligands, agonists, and antagonists of GPCRs, and achieved an area under the ROC curve (AUC) of 0.795, sensitivity of 0.716, specificity of 0.744, and accuracy of 0.733. In addition, we verified that 70% (44 out of 63) of FDA-approved GPCR-targeting drugs were correctly classified into their respective groups. CONCLUSIONS: Studies of ligand–GPCR interaction recognition are important for the characterization of drug action mechanisms. Our GPCR–ligand interaction prediction model can be employed in the pharmaceutical sciences for the efficient virtual screening of putative GPCR-binding agonists and antagonists. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12859-022-04877-7.