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

DOI: 10.1021/jm5011397 DOI Help
PMID: 25238611 PMID Help

Authors: Jennie A. Hutton (Imperial College London) , Victor Goncalves (Imperial College London) , James A. Brannigan (University of York) , Daniel Paape (University of York) , Megan H. Wright (Imperial College London) , Thomas M. Waugh (Imperial College London) , Shirley Roberts (University of York) , Andrew S. Bell (Imperial College London) , Anthony Wilkinson (University of York) , Deborah F. Smith (University of York) , Robin J. Leatherbarrow (Imperial College London) , Edward W. Tate (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 57 (20) , PAGES 8664 - 8670

State: Published (Approved)
Published: October 2014
Diamond Proposal Number(s): 1221 , 7864

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography