title: 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.affiliation: Department of Chemistry, Imperial College London , London SW7 2AZ, U.K.
authors.forename: Jennie A
authors.initials: JA
authors.lastname: Hutton
authors.forename: Victor
authors.initials: V
authors.lastname: Goncalves
authors.forename: James A
authors.initials: JA
authors.lastname: Brannigan
authors.forename: Daniel
authors.initials: D
authors.lastname: Paape
authors.forename: Megan H
authors.initials: MH
authors.lastname: Wright
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Waugh
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Roberts
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Bell
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Wilkinson
authors.forename: Deborah F
authors.initials: DF
authors.lastname: Smith
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Leatherbarrow
authors.forename: Edward W
authors.initials: EW
authors.lastname: Tate
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D057166:High-Throughput Screening Assays / Q000379:methods; D007893:Leishmania donovani / Q000201:enzymology; D018320:Leishmania major / Q000201:enzymology; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase