Active deep learning offers a promising approach for hit discovery starting from limited data by iteratively updating and improving models during screening by applying new data and adapting decisions. Key open questions include how best to explore chemical space, how it compares to non-iterative methods, and how to use it under data scarcity. We present ChemScreener, a multi-task active learning workflow for early drug discovery across large, diverse libraries or chemical spaces. Its Balanced-Ranking acquisition strategy leverages ensemble uncertainty to explore novel chemistry while maintaining hit rate enrichment by prioritizing predicted activity. In five iterative single-dose HTRF screens on WDR5 protein, C... More
Active deep learning offers a promising approach for hit discovery starting from limited data by iteratively updating and improving models during screening by applying new data and adapting decisions. Key open questions include how best to explore chemical space, how it compares to non-iterative methods, and how to use it under data scarcity. We present ChemScreener, a multi-task active learning workflow for early drug discovery across large, diverse libraries or chemical spaces. Its Balanced-Ranking acquisition strategy leverages ensemble uncertainty to explore novel chemistry while maintaining hit rate enrichment by prioritizing predicted activity. In five iterative single-dose HTRF screens on WDR5 protein, ChemScreener increased hit rates from 0.49% (primary HTS screen) to 3 10% (average 5.91%; 104 hits from 1760 compounds). Hits were consolidated, retested with close analogs together in the 269 compounds set and clustered; 44 hit compounds from 81 clusters of 269 compounds set advanced to dose response and filtered by counter HTRF assays. Over 50% of those with IC50 < 45 M were validated as WDR5 binders by DSF. We de novo identified three scaffold series and three singleton scaffolds as the hits. Overall, we demonstrated that ChemScreener can accelerate early hit discovery and yield more diverse chemotypes.Scientific contributionHit identification is a costly, time-intensive stage in drug discovery. We developed ChemScreener, a scalable active learning workflow for early hit discovery that improves hit rate enrichment through iterative screening of small number of compounds and expands chemical diversity by de novo hit scaffolds identified. ChemScreener offers a generalizable, target-specific, ligand-based virtual screening framework that accelerates early discovery and enhances effectiveness across large, diverse chemical libraries.Supplementary Information The online version contains supplementary material available at 10.1186/s13321-026-01204-7.
