DeepREAL: A deep learning powered multi-scale modeling framework for predicting out-of-distribution ligand-induced GPCR activity

Abstract

Motivation: Drug discovery has witnessed intensive exploration of predictive modeling of drug-target physical interactions over two decades. However, a critical knowledge gap needs to be filled for correlating drug-target interactions with clinical outcomes: Predicting genome-wide receptor activities or function selectivity, especially agonist versus antagonist, induced by novel chemicals. Two major obstacles compound the difficulty on this task: Known data of receptor activity is far too scarce to train a robust model in light of genome-scale applications, and real-world applications need to deploy a model on data from various shifted distributions. Results: To address these challenges, we have developed an end-to-end deep learning framework, DeepREAL, for multi-scale modeling of genome-wide ligand-induced receptor activities. DeepREAL utilizes self-supervised learning on tens of millions of protein sequences and pre-trained binary interaction classification to solve the data distribution shift and data scarcity problems. Extensive benchmark studies on G-protein coupled receptors (GPCRs), which simulate real-world scenarios, demonstrate that DeepREAL achieves state-of-the-art performances in out-of-distribution settings. DeepREAL can be extended to other gene families beyond GPCRs.