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

J Med Chem. 2014 Oct 23;57(20):8664-70. doi: 10.1021/jm5011397. Epub 2014 Oct 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Enzyme Inhibitors
  • Acyltransferases
  • glycylpeptide N-tetradecanoyltransferase

Associated data

  • PDB/4CGL
  • PDB/4CGN
  • PDB/4CYN
  • PDB/4CYO
  • PDB/4CYQ