Prediction of GPCR activity using machine learning

GPCRs are the target for one-third of the FDA-approved drugs, however; the development of new drug molecules targeting GPCRs is limited by the lack of mechanistic understanding of the GPCR structure–activity-function relationship. To modulate the GPCR activity with highly specific drugs and minimal side-effects, it is necessary to quantitatively describe the important structural features in the GPCR and correlate them to the activation state of GPCR. In this study, we developed 3 ML approaches to predict the conformation state of GPCR proteins. Additionally, we predict the activity level of GPCRs based on their structure. We leverage the unique advantages of each of the 3 ML approaches, interpretability of XGBoost, minimal feature engineering for 3D convolutional neural network, and graph representation of protein structure for graph neural network. By using these ML approaches, we are able to predict the activation state of GPCRs with high accuracy (91%–95%) and also predict the activation state of GPCRs with low error (MAE of 7.15–10.58). Furthermore, the interpretation of the ML approaches allows us to determine the importance of each of the features in distinguishing between the GPCRs conformations.