Deciphering DEL pocket patterns through contrastive learning
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Abstract
DNA-encoded libraries (DELs) facilitate high-throughput screening of trillions of molecules against protein targets through split-pool synthesis and DNA tagging. Despite their potential, only a few DEL-derived compounds have advanced to clinical trials or reached the market. A better understanding of the defining characteristics of target proteins, particularly those with binding pockets suitable for DEL screening, is critical to improving success rates. However, existing approaches remain limited in assessing pocket flexibility and functional similarity. Here, we present ErePOC, a pocket representation model based on contrastive learning with ESM-2 embeddings to address these challenges. ErePOC captures both structural and functional features of binding pockets, enabling identification of shared characteristics among DEL targets. By integrating analyses of low-dimensional physicochemical properties and high-dimensional ErePOC embeddings, we provide a comprehensive view of DEL target space. With 98% precision in downstream classification tasks, ErePOC demonstrates high performance in pocket representation, which is then applied to predict human proteins suitable for DEL screening, with enrichment uncovered across 18 functional categories. This work establishes a framework for enhancing DEL-based drug discovery through more effective target selection and pocket similarity analysis.
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- Authors
- Zhang, W., Wang, Y., Zhan, R., Qian, R., Hu, Q., & Huang, J.
- Affiliations
- Westlake University (CN)
- Corresponding author
- Huang, Jing
- Venue
- Nature Communications
- Published
- 2026-02-16
- Volume
- 17
- Issue
- 1
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W7129060316
- Cited by
- 2
- References
- 48
- Citations by year
- 2026: 2
- FWCI
- 7.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Westlake University
- National Natural Science Foundation of China (2023C03109, 32171247, 32501101, 2024SSYS0036)
- Natural Science Foundation of Zhejiang Province (LQ23F020011, 2024SSYS0036)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- DNA-encoded libraries, protein pockets, contrastive learning, ESM-2 embeddings, physicochemical properties, protein functional classification, high-throughput screening, drug discovery
- MeSH terms
- Machine Learning, Binding Sites, DNA, Humans, Models, Molecular, Protein Binding, Proteins, Small Molecule Libraries, Drug Discovery
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