Discovery of Plasmodium vivax N-myristoyltransferase inhibitors: screening, synthesis, and structural characterization of their binding mode

J Med Chem. 2012 Apr 12;55(7):3578-82. doi: 10.1021/jm300040p. Epub 2012 Apr 3.

Abstract

N-Myristoyltransferase (NMT) is a prospective drug target against parasitic protozoa. Herein we report the successful discovery of a series of Plasmodium vivax NMT inhibitors by high-throughput screening. A high-resolution crystal structure of the hit compound in complex with NMT was obtained, allowing understanding of its novel binding mode. A set of analogues was designed and tested to define the chemical groups relevant for activity and selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / antagonists & inhibitors*
  • Acyltransferases / chemistry
  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Crystallography, X-Ray
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Models, Molecular
  • Molecular Structure
  • Plasmodium vivax / enzymology*
  • Protein Binding
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Structure-Activity Relationship

Substances

  • 3-butyl-4-((2-cyanoethyl)thio)-6-methoxy-2-methyl-quinoline
  • Antimalarials
  • Isoenzymes
  • Quinolines
  • Acyltransferases
  • glycylpeptide N-tetradecanoyltransferase

Associated data

  • PDB/4A95