title: Identification and structure solution of fragment hits against kinetoplastid N-myristoyltransferase.
abstract: Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis. Pyrazole sulfonamide (DDD85646), a potent inhibitor of TbNMT, has been identified in previous studies; however, poor central nervous system exposure restricts its use to the haemolymphatic form (stage 1) of the disease. In order to identify new chemical matter, a fragment screen was carried out by ligand-observed NMR spectroscopy, identifying hits that occupy the DDD85646 binding site. Crystal structures of hits from this assay have been obtained in complex with the closely related NMT from Leishmania major, providing a structural starting point for the evolution of novel chemical matter.
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland.
authors.forename: David A
authors.initials: DA
authors.lastname: Robinson
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
mesh_terms: D000217:Acyltransferases / Q000737:chemistry* / Q000378:metabolism*; D000631:Aminopyridines / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D016830:Kinetoplastida / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism*; D014346:Trypanosoma brucei brucei / Q000737:chemistry* / Q000201:enzymology*; D000096926:Benzenesulfonamides
chemical_list: D000217:Acyltransferases; D000631:Aminopyridines; D013449:Sulfonamides; C549249:DDD 85646; D000096926:Benzenesulfonamides; C050480:glycylpeptide N-tetradecanoyltransferase
keywords: African trypanosomiasis; N-myristoyltransferase; Trypanosoma brucei