Deep contrastive learning enables genome-wide virtual screening

Abstract

AbstractNumerous protein-coding genes are associated with human diseases, yet approximately 90% of them lack targeted therapeutic intervention. While conventional computational methods such as molecular docking have facilitated the discovery of potential hit compounds, the development of genome-wide virtual screening against the expansive chemical space remains a formidable challenge. Here we introduce DrugCLIP, a novel framework that combines contrastive learning and dense retrieval to achieve rapid and accurate virtual screening. Compared to traditional docking methods, DrugCLIP improves the speed of virtual screening by several orders of magnitude. In terms of performance, DrugCLIP not only surpasses docking and other deep learning-based methods across two standard benchmark datasets but also demonstrates high efficacy in wet-lab experiments. Specifically, DrugCLIP successfully identified agonists with < 100 nM affinities for 5HT2AR, a key target in psychiatric diseases. For another target NET, whose structure is newly solved and not included in the training set, our method achieved a hit rate of 15%, with 12 diverse molecules exhibiting affinities better than Bupropion. Additionally, two chemically novel inhibitors were validated by structure determination with Cryo-EM. Building on this foundation, we present the results of a pioneering trillion-scale genome-wide virtual screening, encompassing approximately 10,000 AlphaFold2 predicted proteins within the human genome and 500 million molecules from the ZINC and Enamine REAL database. This work provides an innovative perspective on drug discovery in the post-AlphaFold era, where comprehensive targeting of all disease-related proteins is within reach.