PXD072258-1

PXD072258 is an original dataset announced via ProteomeXchange.

Title	Discovery of novel covalent ligands with AlphaFold3
Description	Covalent inhibitors are a prominent modality for research and therapeutic tools. However, a scarcity of computational methods for their discovery slows progress in this field. AI models such as AlphaFold3 (AF3) have shown accuracy in ligand pose prediction, but their applicability for virtual screening campaigns was not assessed. We show that AF3 co-folding predictions and an associated predicted confidence metric ranks true covalent binders with near-optimal classification over property-matched decoys, significantly outperforming state-of-the-art covalent docking tools for a set of protein kinases. In a prospective virtual screening campaign against the model kinase BTK, we discovered a chemically distinct, novel, covalent small molecule that displays potent inhibition in vitro and in cells while maintaining marked kinome and proteomic selectivity. Co-crystallography validated the sub-angstrom accuracy of the predicted AF3 binding mode. These results demonstrate that AF3 can be practically used to discover novel chemical matter for kinases, one of the most prolific families of drug targets.
HostingRepository	PRIDE
AnnounceDate	2026-04-06
AnnouncementXML	Submission_2026-04-05_17:34:19.152.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Ronen Gabizon
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 240

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-21 06:52:03	ID requested
⏵ 1	2026-04-05 17:34:20	announced

Shamir Y, Gabizon R, Rogel A, Lin DY, Andreotti AH, London N, Discovery of Covalent Ligands with AlphaFold3. J Am Chem Soc, 148(12):13043-13054(2026) [pubmed]

10.1021/jacs.5c22222;

submitter keyword: BTK,Alphafold

Nir London
contact affiliation	Department of Chemical and Structural Biology, Weizmann Institute
contact email	nir.london@weizmann.ac.il
lab head
Ronen Gabizon
contact affiliation	Department of Chemical and Structural Biology, Weizmann Institute of Science
contact email	ronen.gabizon@weizmann.ac.il
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD072258
     1. Label: PRIDE project
     2. Name: Discovery of novel covalent ligands with AlphaFold3