6BTL

Crystal structure of Trypanothione Reductase from Trypanosoma brucei in complex with inhibitor RD117 1-[2-(Piperazin-1-yl)ethyl]-5-{5-[1-(pyrrolidin-1-yl)cyclohexyl]-1,3-thiazol-2-yl}-1H-indole

Summary for 6BTL

• Entry DOI: 10.2210/pdb6btl/pdb
• Related: 4NEV
• Descriptor: Trypanothione reductase, FLAVIN-ADENINE DINUCLEOTIDE, SULFATE ION, ... (7 entities in total)
• Functional Keywords: inhibitor, complex, sleeping sickness, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Trypanosoma brucei brucei TREU927
• Total number of polymer chains: 2
• Total formula weight: 110819.70

Authors

Bryson, S.,De Gasparo, R.,Krauth-Siegel, R.L.,Diederich, F.,Pai, E.F. (deposition date: 2017-12-06, release date: 2018-06-06, Last modification date: 2024-10-23)

Primary citation

De Gasparo, R.,Brodbeck-Persch, E.,Bryson, S.,Hentzen, N.B.,Kaiser, M.,Pai, E.F.,Krauth-Siegel, R.L.,Diederich, F.
Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma.
ChemMedChem, 13:957-967, 2018

PubMed Abstract: 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 (K ) against Trypanosoma (T.) brucei TR and T. cruzi TR and in vitro activities (half-maximal inhibitory concentration, IC ) 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.

PubMed: 29624890
DOI: 10.1002/cmdc.201800067

Experimental method

X-RAY DIFFRACTION (2.797 Å)