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. AVAILABILITY AND IMPLEMENTATION All data used are downloaded from Pfam (Mistry et al., 2020), GLASS (Chan et al., 2015) and IUPHAR/BPS and the data from reference (Sakamuru et al., 2021). Readers are directed to their official website for original data. Code is available on GitHub https//github.com/XieResearchGroup/DeepREAL. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.