6bu7

Crystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor RD130 1-[2-(Piperidin-4-yl)ethyl]-5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole

spinqualitylabelsall models 6bu7, resolution 2.73Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6bu7 is a 2 chain structure with sequence from Tryb2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EPE, FAD, GOL, RD0, SO4 Related: 4nev, 6btl Gene: Tb10.406.0520 (TRYB2) Activity: Trypanothione-disulfide reductase, with EC number 1.8.1.12 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure-based design. The best inhibitors were freely soluble and showed competitive inhibition constants (Ki ) against Trypanosoma (T.) brucei TR and T. cruzi TR and in vitro activities (half-maximal inhibitory concentration, IC50 ) against these parasites in the low micromolar range, with high selectivity against human glutathione reductase. X-ray co-crystal structures confirmed the binding of the ligands to the hydrophobic wall of the "mepacrine binding site" with the new, solubility-providing vectors oriented toward the surface of the large active site. Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma.,De Gasparo R, Brodbeck-Persch E, Bryson S, Hentzen NB, Kaiser M, Pai EF, Krauth-Siegel RL, Diederich F ChemMedChem. 2018 May 8;13(9):957-967. doi: 10.1002/cmdc.201800067. Epub 2018 Apr, 6. PMID:29624890 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Trypanothione reductase

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