Structure-based design of potent and selective Leishmania N-myristoyltransferase inhibitors.

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.

• 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 20 Pg. 8664-70 (Oct 23 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25238611 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Acyltransferases
• glycylpeptide N-tetradecanoyltransferase

Topics

• Acyltransferases (antagonists & inhibitors, chemistry, metabolism)
• Chemistry Techniques, Synthetic
• Crystallography, X-Ray
• Enzyme Inhibitors (chemical synthesis, chemistry, metabolism, pharmacology)
• High-Throughput Screening Assays (methods)
• Leishmania donovani (enzymology)
• Leishmania major (enzymology)
• Models, Molecular
• Structure-Activity Relationship