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Development of small-molecule Trypanosoma brucei n-myristoyltransferase inhibitors: discovery and optimisation of a novel binding mode

DOI: 10.1002/cmdc.201500301 DOI Help
PMID: 26395087 PMID Help

Authors: Daniel Spinks (University of Dundee) , Victoria Smith (University of Dundee) , Stephen Thompson (University of Dundee) , David Robinson (University of Dundee) , Torsten Luksch (University of Dundee) , Alasdair Smith (University of Dundee) , Leah S. Torrie (University of Dundee) , Stuart Mcelroy (University of Dundee) , Laste Stojanovski (University of Dundee) , Suzanne Norval (University of Dundee) , Iain T. Collie (University of Dundee) , Irene Hallyburton (University of Dundee) , Bhavya Rao (University of Dundee) , Stephen Brand (University of Dundee) , Ruth Brenk (University of Dundee) , Julie A. Frearson (University of Dundee) , Kevin D. Read (University of Dundee) , Paul G. Wyatt (University of Dundee) , Ian H. Gilbert (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemmedchem , VOL 10 , PAGES 1821 - 1836

State: Published (Approved)
Published: November 2015

Open Access Open Access

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.

Journal Keywords: human African trypanosomiasis (HAT); medicinal chemistry; N-myristoyltransferase; structure-based drug design; Trypanosoma brucei

Diamond Keywords: Sleeping Sickness

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography

Other Facilities: ID14–1 at ESRF

Added On: 16/12/2015 14:08

ChemMedChem - 2015 - Spinks - Development of Small%E2%80%90Molecule Trypanosoma brucei N%E2%80%90Myristoyltransferase Inhibitors Discovery.pdf

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)