Structure-Based Design of Potent and Selective Leishmania N-Myristoyltransferase Inhibitors

被引：47

作者：

Hutton, Jennie A. ^{[1
]}

Goncalves, Victor ^{[1
]}

Brannigan, James A. ^{[2
]}

Paape, Daniel ^{[3
,4
]}

Wright, Megan H. ^{[1
]}

Waugh, Thomas M. ^{[1
]}

Roberts, Shirley M. ^{[2
]}

Bell, Andrew S. ^{[1
]}

Wilkinson, Anthony J. ^{[2
]}

Smith, Deborah F. ^{[3
,4
]}

Leatherbarrow, Robin J. ^{[1
]}

Tate, Edward W. ^{[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] Univ York, Ctr Immunol & Infect, Dept Biol, York YO10 5DD, N Yorkshire, England

[4] Univ York, Hull York Med Sch, York YO10 5DD, N Yorkshire, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 20期

基金：

英国工程与自然科学研究理事会; 英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

MYRISTOYL-COA; DRUG TARGET; BINDING; PROTEINS; RESISTANCE; DISCOVERY; MALARIA;

D O I：

10.1021/jm5011397

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibitors of Leishmania N-myristoyltransferase (NMT), a potential target for the treatment of leishmaniasis, obtained from a high-throughput screen, were resynthesized to validate activity. Crystal structures bound to Leishmania major NMT were obtained, and the active diastereoisomer of one of the inhibitors was identified. On the basis of structural insights, enzyme inhibition was increased 40-fold through hybridization of two distinct binding modes, resulting in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme.

引用

页码：8664 / 8670

页数：7

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