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Review
. 2025 Sep;9(9):634-645.
doi: 10.1038/s41570-025-00737-z. Epub 2025 Jul 23.

Protein-ligand data at scale to support machine learning

Aled M Edwards  1 , Dafydd R Owen  2 ; Structural Genomics Consortium Target 2035 Working Group
Collaborators, Affiliations
Review

Protein-ligand data at scale to support machine learning

Aled M Edwards et al. Nat Rev Chem. 2025 Sep.

Abstract

Target 2035 is a global initiative that aims to develop a potent and selective pharmacological modulator, such as a chemical probe, for every human protein by 2035. Here, we describe the Target 2035 roadmap to develop computational methods to improve small-molecule hit discovery, which is a key bottleneck in the discovery of chemical probes. Large, publicly available datasets of high-quality protein-small-molecule binding data will be created using affinity-selection mass spectrometry and DNA-encoded chemical library screening. Positive and negative data will be made openly available, and the machine learning community will be challenged to use these data to build models and predict new, diverse small-molecule binders. Iterative cycles of prediction and testing will lead to improved models and more successful predictions. By 2030, Target 2035 will have identified experimentally verified hits for thousands of human proteins and advanced the development of open-access algorithms capable of predicting hits for proteins for which there are not yet any experimental data.

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Conflict of interest statement

Competing interests: D.-A.C., K.S. and D.R.O. are shareholders in Pfizer Inc. The Cernak Lab’s research has been supported by MilliporeSigma, Johnson & Johnson, Relay Therapeutics, Merck & Co., Inc., SPT Labtech, National Defense Medical Center, Shanghai University of Traditional Chinese Medicine, Ministry of Education Taiwan, and Entos, Inc. T.C. has consulted for the University of Dundee Drug Discovery Unit, Scorpion Therapeutics, Relay Therapeutics, Amgen, Genentech, Janssen, Pfizer, Vertex, MilliporeSigma, the US Food & Drug Administration, Gilead, AbbVie, Corteva, Syngenta, Firmenich, Biogen, Bayer, UCB Biopharma, National Taiwan University, AstraZeneca, Grunenthal, and Iambic Therapeutics (previously known as Entos, Inc.). He holds equity in Scorpion Therapeutics and is a co-founder and equity holder at Iambic Therapeutics. B.H.-K. is a co-Founder of the MAQC (Massive Analysis and Quality Control) Society and part of the Scientific Advisory Board of: Consortium de recherche biopharmaceutique (CQDM), Quebec, Canada, Break Through Cancer, Commonwealth Cancer Consortium, United States, Canadian Institute of Health Research–Institute of Genetics, Canada, Cancer Grand Challenges, United Kingdom, Shriners Children, United States. He is part of the Executive Committee of the Terry Fox Digital Health and Discovery Platform, Canada and in the Board of Directors of AACR International–Canada, The American Association for Cancer Research, United States. D.W.Y. is co-founder and shareowner of Deliver Therapeutics. I.V.H. is part of the Board of Directors of TenAces Biosciences. A.K. serves on the SAB of Cilcare, Sulfateq BV and Heartbeat.bio. J.C.M. may hold stock options in Astrazeneca. A.M.-F. is the Board Chair of SGC and Conscience. She is also a shareholder for Bayer AG and an external consultant for Nuvisan ICB GmbH. N.B.-B. is on the SAB for Oxford Vacmedix and holds shares of Exact Sciences. A.T. is co-founder of Predictive LLC. A.S.D. holds stocks in DANAHER. F.K. is a shareholder in Evotec SE. A.F.-M. possess Bayer AG shares. A.A.A. is a consultant to Darwin Health and has received grant funding from Vivan Therapeutics and AtG Therapeutics. D.P. holds stock in Novartis.

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