Identification and structure solution of fragment hits against kinetoplastid N-myristoyltransferase

David A. Robinson; Paul G. Wyatt

doi:10.1107/S2053230X15003040

Identification and structure solution of fragment hits against kinetoplastid N-myristoyltransferase

David A. Robinson, Paul G. Wyatt (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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.

Original language	English
Pages (from-to)	586-593
Number of pages	8
Journal	Acta Crystallographica Section F: Structural Biology Communications
Volume	71
Issue number	5
DOIs	https://doi.org/10.1107/S2053230X15003040
Publication status	Published - May 2015

Keywords

African trypanosomiasis
Molecular parasitology - advances in biology and supporting drug discovery
N-myristoyltransferase
Trypanosoma brucei

ASJC Scopus subject areas

Biochemistry
Biophysics
Genetics
Structural Biology
Condensed Matter Physics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1107/S2053230X15003040

Cite this

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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.",

keywords = "African trypanosomiasis, Molecular parasitology - advances in biology and supporting drug discovery, N-myristoyltransferase, Trypanosoma brucei",

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month = may,

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language = "English",

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pages = "586--593",

journal = "Acta Crystallographica Section F: Structural Biology Communications",

issn = "2053-230X",

publisher = "International Union of Crystallography",

number = "5",

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T1 - Identification and structure solution of fragment hits against kinetoplastid N-myristoyltransferase

AU - Robinson, David A.

AU - Wyatt, Paul G.

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AB - 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.

KW - African trypanosomiasis

KW - Molecular parasitology - advances in biology and supporting drug discovery

KW - N-myristoyltransferase

KW - Trypanosoma brucei

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DO - 10.1107/S2053230X15003040

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Identification and structure solution of fragment hits against kinetoplastid N-myristoyltransferase

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)

Cite this

Identification and structure solution of fragment hits against kinetoplastid N-myristoyltransferase

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Discovery and Development of Drug Candidates for Neglected Diseases (joint with industrial partner)

Cite this