Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
No Canadian affiliation. An affiliation-only frame — the usual design — would never have seen this work. It is one of the works that make the case for inverting the frame.
Machine scores (provisional)
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
- Teacher spread
- 0.228 · how far apart the two teachers sit on this one work
- Validation status
score_only:v0-immature-baseline· verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it
Abstract
Covalent probes can display unmatched potency, selectivity, and duration of action; however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening, but such electrophilic fragments were considered nonselective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against 10 cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. In contrast, we found hits for most targets. Combining our approach with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2 and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlights the potential of electrophile-fragment screening as a practical and efficient tool for covalent-ligand discovery.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
The record
- Venue
- Journal of the American Chemical Society
- Topic
- Click Chemistry and Applications
- Field
- Chemistry
- Canadian institutions
- —
- Funders
- Medical Research CouncilGenome CanadaFundação de Amparo à Pesquisa do Estado de São PauloMinistry of Science and Technology, IsraelNederlandse Organisatie voor Wetenschappelijk OnderzoekWellcome TrustNovartis PharmaOntario Genomics InstituteEuropean Federation of Pharmaceutical Industries and AssociationsInnovative Medicines InitiativeWellcomeMerck KGaAOntario Ministry of Research, Innovation and ScienceOntario GenomicsRising Tide FoundationPfizerIsrael Science FoundationIsrael Cancer Research Fund
- Keywords
- ChemistryElectrophileCovalent bondLigand efficiencyCombinatorial chemistryDrug discoveryFragment (logic)Ligand (biochemistry)CysteineSelectivityDeubiquitinating enzymeStereochemistryHigh-throughput screeningEnzymeBiochemistryOrganic chemistryReceptorGeneUbiquitin
- Has abstract in OpenAlex
- yes