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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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Supplementary files

Article information


Submitted
02 Jul 2018
Accepted
07 Dec 2018
First published
10 Dec 2018

This article is Open Access

Med. Chem. Commun., 2019,10, 263-267
Article type
Research Article

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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