Deep contrastive learning enables genome-wide virtual screening
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Abstract
Recent breakthroughs in protein structure prediction have opened new avenues for genome-wide drug discovery, yet existing virtual screening methods remain computationally prohibitive. We present DrugCLIP, a contrastive learning framework that achieves ultrafast and accurate virtual screening, up to 10 million times faster than docking, while consistently outperforming various baselines on in silico benchmarks. In wet-lab validations, DrugCLIP achieved a 15% hit rate for norepinephrine transporter, and structures of two identified inhibitors were determined in complex with the target protein. For thyroid hormone receptor interactor 12, a target that lacks holo structures and small-molecule binders, DrugCLIP achieved a 17.5% hit rate using only AlphaFold2-predicted structures. Finally, we released GenomeScreenDB, an open-access database providing precomputed results for ~10,000 human proteins screened against 500 million compounds, pioneering a drug discovery paradigm in the post-AlphaFold era.
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Flagged first, then by citations
- Authors
- Jia, Y., Gao, B., Tan, J., Zheng, J., Hong, X., Zhu, W., Tan, H., Xiao, Y., Tan, L., Cai, H., Huang, Y., Deng, Z., Wu, X., Jin, Y., Yuan, Y., Tian, J., He, W., Ma, W., Zhang, Y., Liu, L., Yan, C., Zhang, W., & Lan, Y.
- Affiliations
- Tsinghua University (CN)
- Tsinghua-Peking Center for Life Sciences, Beijing, China.
- School of Life Sciences, Tsinghua University, Beijing, China.
- Peking University (CN)
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
- Institute for AI Industry Research (AIR), Tsinghua University, Beijing, China.
- Corresponding author
- Lan, Yanyan
- ORCID
- Venue
- Science
- Published
- 2026-01-08
- Volume
- 391
- Issue
- 6781
- Pages
- eads9530-eads9530
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W7119529911
- Cited by
- 66
- References
- 18
- Citations by year
- 2026: 66
- FWCI
- 239.61
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (32341016, 32171204, 22137005, T2488301)
- National key R&D program of China (2021YFF1201600, 2020YFA0509301, 2021ZD0203303, 2021ZD0200306)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- virtual screening, contrastive learning, protein structure prediction, AlphaFold2, norepinephrine transporter, protein-ligand binding prediction, computational drug discovery
- MeSH terms
- Deep Learning, Humans, Protein Conformation, Genome, Human, Norepinephrine Plasma Membrane Transport Proteins, Small Molecule Libraries, Drug Discovery, Molecular Docking Simulation
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