Chemical and Computational Methods for the Characterization of Covalent Reactive Groups for the Prospective Design of Irreversible Inhibitors

被引：250

作者：

Flanagan, Mark E. ^{[1
]}

Abramite, Joseph A. ^{[1
]}

Anderson, Dennis P. ^{[1
]}

Aulabaugh, Ann ^{[1
]}

Dahal, Upendra P.

Gilbert, Adam M. ^{[1
]}

Li, Chao ^{[1
]}

Montgomery, Justin ^{[1
]}

Oppenheimer, Stacey R. ^{[1
]}

Ryder, Tim ^{[2
]}

Schuff, Brandon P. ^{[1
]}

Uccello, Daniel P. ^{[1
]}

Walker, Gregory S. ^{[2
]}

Wu, Yan

Brown, Matthew F. ^{[1
]}

Chen, Jinshan M. ^{[1
]}

Hayward, Matthew M. ^{[1
]}

Noe, Mark C. ^{[1
]}

Obach, R. Scott ^{[2
]}

Philippe, Laurence ^{[1
]}

Shanmugasundaram, Veerabahu ^{[1
]}

Shapiro, Michael J. ^{[1
]}

Starr, Jeremy ^{[1
]}

Stroh, Justin ^{[1
]}

Che, Ye ^{[1
]}

机构：

[1] Pfizer Inc, Ctr Chem Innovat & Excellence, Groton, CT 06340 USA

[2] Pfizer Inc, Dept Pharmacokinet Dynam & Metab, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 23期

关键词：

ACCEPTOR REACTIVITY; TOXICITY; BINDING; GLUTATHIONE; SELECTIVITY; PREDICTION; THIOLS;

D O I：

10.1021/jm501412a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Interest in drugs that covalently modify their target is driven by the desire for enhanced efficacy that can result from the silencing of enzymatic activity until protein resynthesis can occur, along with the potential for increased selectivity by targeting uniquely positioned nucleophilic residues in the protein. However, covalent approaches carry additional risk for toxicities or hypersensitivity reactions that can result from covalent modification of unintended targets. Here we describe methods for measuring the reactivity of covalent reactive groups (CRGs) with a biologically relevant nucleophile, glutathione (GSH), along with kinetic data for a broad array of electrophiles. We also describe a computational method for predicting electrophilic reactivity, which taken together can be applied to the prospective design of thiol-reactive covalent inhibitors.

引用

页码：10072 / 10079

页数：8

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