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

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• 作者：Jennie A. Hutton ; Victor Goncalves ; James A. Brannigan ; Daniel Paape ; Megan H. Wright ; Thomas M. Waugh ; Shirley M. Roberts ; Andrew S. Bell ; Anthony J. Wilkinson ; Deborah F. Smith ; Robin J. Leatherbarrow ; Edward W. Tate
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：October 23, 2014
• 年：2014
• 卷：57
• 期：20
• 页码：8664-8670
• 全文大小：391K
• ISSN：1520-4804

文摘

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.