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Issue 2, 2019
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Design and characterization of a heterocyclic electrophilic fragment library for the discovery of cysteine-targeted covalent inhibitors

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Abstract

A fragment library of electrophilic small heterocycles was characterized through cysteine-reactivity and aqueous stability tests that suggested their potential as covalent warheads. The analysis of theoretical and experimental descriptors revealed correlations between the electronic properties of the heterocyclic cores and their reactivity against GSH that are helpful in identifying suitable fragments for cysteines with specific nucleophilicity. The most important advantage of these fragments is that they show only minimal structural differences from non-electrophilic counterparts. Therefore, they could be used effectively in the design of targeted covalent inhibitors with minimal influence on key non-covalent interactions.

Graphical abstract: Design and characterization of a heterocyclic electrophilic fragment library for the discovery of cysteine-targeted covalent inhibitors

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Publication details

The article was received on 02 Jul 2018, accepted on 07 Dec 2018 and first published on 10 Dec 2018


Article type: Research Article
DOI: 10.1039/C8MD00327K
Citation: Med. Chem. Commun., 2019,10, 263-267
  • Open access: Creative Commons BY-NC license
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    Design and characterization of a heterocyclic electrophilic fragment library for the discovery of cysteine-targeted covalent inhibitors

    A. Keeley, P. Ábrányi-Balogh and G. M. Keserű, Med. Chem. Commun., 2019, 10, 263
    DOI: 10.1039/C8MD00327K

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