Structure-based Design of Potent and Selective Leishmania N-myristoyltransferase Inhibitors

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Sep 20

PMID 25238611

Citations 33

Authors

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

Affiliations

Soon will be listed here.

Abstract

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.

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