ArticleChembiochem : a European journal of chemical biology2026
Mapping Functionally Relevant Tractable Lysines of Challenging Protein Targets by Covalent Fragment Screening.
Article in Chembiochem : a European journal of chemical biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Covalent fragment screening has become an established strategy for identifying targetable amino acid residues or viable chemical starting points against challenging protein targets. In recent years, lysine has received growing interest as a nucleophilic residue suitable for covalent labelling. Herein, we present a lysine-targeting covalent fragment library covering a wide range of warheads. The reactivity and stability of the library members have been systematically characterised, and the library has been subsequently screened against a set of therapeutically relevant and challenging protein targets. We have discovered suitable warheads against the targets and characterised binding sites via enzymatic digestion and modelling. These findings highlight the potential of lysine-targeting covalent chemistry to expand binding site discovery and to support warhead optimisation for diverse protein targets in both medicinal chemistry and chemical biology applications.
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