title: Development of Small-Molecule Trypanosoma brucei N-Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode.
abstract: The enzyme N-myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high-throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X-ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X-ray crystallography/structure-based design approach, the benzomorpholinone series was further optimised, increasing activity against T. brucei NMT by >1000-fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T. brucei.
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Spinks
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Smith
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Thompson
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Robinson
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Torsten
authors.initials: T
authors.lastname: Luksch
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Smith
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Leah S
authors.initials: LS
authors.lastname: Torrie
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: McElroy
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Laste
authors.initials: L
authors.lastname: Stojanovski
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Iain T
authors.initials: IT
authors.lastname: Collie
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Hallyburton
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Bhavya
authors.initials: B
authors.lastname: Rao
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Brand
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK. i.h.gilbert@dundee.ac.uk.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase
keywords: N-myristoyltransferase; Trypanosoma brucei; human African trypanosomiasis (HAT); medicinal chemistry; structure-based drug design