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

被引：57

作者：

Keeley, A. ^{[1
]}

Abranyi-Balogh, P. ^{[1
]}

Keseru, G. M. ^{[1
]}

机构：

[1] Hungarian Acad Sci, Res Ctr Nat Sci, Med Chem Res Grp, Magyar Tudosok Krt 2, H-1117 Budapest, Hungary

来源：

MEDCHEMCOMM | 2019年 / 10卷 / 02期

关键词：

D O I：

10.1039/c8md00327k

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：263 / 267

页数：5

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