5ag5

CRYSTAL STRUCTURE OF LEISHMANIA MAJOR N-MYRISTOYLTRANSFERASE (NMT) WITH BOUND MYRISTOYL-COA AND A THIAZOLIDINONE LIGAND

spinqualitylabelsall models 5ag5, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ag5 is a 1 chain structure with sequence from Leishmania major. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2Å Ligands: DLR, MYA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q4Q5S8_LEIMA Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins (By similarity). Publication Abstract from PubMed 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. Development of Small-Molecule Trypanosoma brucei N-Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode.,Spinks D, Smith V, Thompson S, Robinson DA, Luksch T, Smith A, Torrie LS, McElroy S, Stojanovski L, Norval S, Collie IT, Hallyburton I, Rao B, Brand S, Brenk R, Frearson JA, Read KD, Wyatt PG, Gilbert IH ChemMedChem. 2015 Sep 23. doi: 10.1002/cmdc.201500301. PMID:26395087 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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