Discovery of Plasmodium vivax N-Myristoyltransferase Inhibitors: Screening, Synthesis, and Structural Characterization of their Binding Mode

被引：62

作者：

Goncalves, Victor ^{[1
]}

Brannigan, James A. ^{[2
]}

Whalley, David ^{[3
]}

Ansell, Keith H. ^{[3
]}

Saxty, Barbara ^{[3
]}

Holder, Anthony A. ^{[4
]}

Wilkinson, Anthony J. ^{[2
]}

Tate, Edward W. ^{[1
]}

Leatherbarrow, Robin J. ^{[1
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AZ, England

[2] Univ York, Dept Chem, Struct Biol Lab, York YO10 5DD, N Yorkshire, England

[3] MRC Technol, Ctr Therapeut Discovery, London NW7 1AD, England

[4] MRC Natl Inst Med Res, London NW7 1AA, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 07期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会; 英国惠康基金;

关键词：

DRUG TARGET; DERIVATIVES; ANTAGONISTS; PARASITES; MALARIA;

D O I：

10.1021/jm300040p

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

N-Myristoyltransferase (NMT) is a prospective drug target against parasitic protozoa. Herein we report the successful discovery of a series of Plasmodium vivax NMT inhibitors by high-throughput screening. A high-resolution crystal structure of the hit compound in complex with NMT was obtained, allowing understanding of its novel binding mode. A set of analogues was designed and tested to define the chemical groups relevant for activity and selectivity.

引用

页码：3578 / 3582

页数：5

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