ArticleJournal of medicinal chemistry2025
Size-Dependent Target Engagement of Covalent Probes.
Article in Journal of medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
5 citing papers in PubMed.
- Mapping Functionally Relevant Tractable Lysines of Challenging Protein Targets by Covalent Fragment Screening.Chembiochem : a European journal of chemical biology · 2026Article
- Mapping the SHP2 Allosteric Pocket With Target-Biased Covalent Fragments.Chembiochem : a European journal of chemical biology · 2026Article
- Normalizing Covalent Potency for Electrophilicity with Ligand Reactivity Efficiency.Journal of medicinal chemistry · 2026Review
- A practical method for determining the rate of covalent modification of fragments and leads.Nature communications · 2025Article
- A Fragment-Based Electrophile-First Approach to Target Histidine with Aryl-Fluorosulfates: Application to hMcl-1.Journal of medicinal chemistry · 2025Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Labeling proteins with covalent ligands is finding increasing use in proteomics applications, including identifying nucleophilic residues amenable for labeling and in the development of targeted covalent inhibitors (TCIs). Labeling efficiency is measured by the covalent occupancy of the target or by biochemical activity. Here, we investigate how these observed quantities relate to the intrinsic parameters of complex formation, namely, noncovalent affinity and covalent reactivity, and to experimental conditions, including incubation time and ligand concentration. It is shown that target engagement is beneficially driven by noncovalent recognition for lead-like compounds, which are appropriate starting points for targeted covalent inhibitors owing to their easily detectable occupancy and fixed binding mode, facilitating optimization. In contrast, labeling by fragment-sized compounds is inevitably reactivity-driven as their small size limits noncovalent affinity. They are well-suited for exploring ligandable nucleophilic residues, while small fragments are less appropriate starting points for TCI development.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.