4uwi

Crystal structure of Aspergillus fumigatus N-myristoyl transferase in complex with myristoyl CoA and a pyrazole sulphonamide ligand

spinqualitylabelsall models 4uwi, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4uwi is a 1 chain structure with sequence from Aspergillus fumigatus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: MYA, XMQ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NMT_ASPFU Adds a myristoyl group to the N-terminal glycine residue of certain cellular proteins. Publication Abstract from PubMed Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood-brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT. Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei N-Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African Trypanosomiasis.,Brand S, Norcross NR, Thompson S, Harrison JR, Smith VC, Robinson DA, Torrie LS, McElroy SP, Hallyburton I, Norval S, Scullion P, Stojanovski L, Simeons FR, van Aalten D, Frearson JA, Brenk R, Fairlamb AH, Ferguson MA, Wyatt PG, Gilbert IH, Read KD J Med Chem. 2014 Nov 20. PMID:25412409 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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