Fine-Tuned Deep Transfer Learning Models for LargeScreenings of Safer Drugs Targeting Class A GPCRs

G protein-coupled receptors (GPCRs) remain a focal point of research due to their critical roles in cell signaling and their prominence as drug targets. However, directly linking drug efficacy to the receptor-mediated activation of specific intracellular transducers and the resulting physiological outcomes remains challenging. It is unclear whether the enhanced therapeutic window of certain drugsdefined as the dose range that provides effective therapy with minimal side effectsstems from their low intrinsic efficacy across all signaling pathways or ligand bias, wherein specific transducer subtypes are preferentially activated in a given cellular system compared to a reference ligand. Accurately predicting safer compounds, through either low intrinsic efficacy or ligand bias, would greatly advance drug development. While AI models hold promise for such predictions, the development of deep learning models capable of reliably forecasting GPCR ligands with defined bioactivities remains challenging, largely due to the limited availability of high-quality data. To address this, we pretrained a model on receptor sequences and ligand data sets across all class A GPCRs and then refined it to predict low-efficacy compounds or biased agonists for individual class A GPCRs. This was achieved using transfer learning and a neural network incorporating natural language processing of target sequences and receptor mutation effects on signaling. These two fine-tuned modelsone for low-efficacy agonists and one for biased agonistsare available on demand for each class A GPCR and enable virtual screening of large chemical libraries, thereby facilitating the discovery of compounds with potentially improved safety profiles.