5AG5: Crystal Structure Of Leishmania Major N- Myristoyltransferase (nmt) With Bound Myristoyl-coa And A Thiazolidinone Ligand

Citation:
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.
PDB ID: 5AG5Download
MMDB ID: 134179
PDB Deposition Date: 2015/1/29
Updated in MMDB: 2016/05
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 5AG5: monomeric; determined by author and by software (PISA)
Molecular Components in 5AG5
Label Count Molecule
Protein (1 molecule)
1
Glycylpeptide N-tetradecanoyltransferase
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

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