Binding to large enzyme pockets: small-molecule inhibitors of trypanothione reductase
Abstract The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target a...
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| Hauptverfasser: | , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
April 30, 2014
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| In: |
ChemMedChem
Year: 2014, Jahrgang: 9, Heft: 8, Pages: 1880-1891 |
| ISSN: | 1860-7187 |
| DOI: | 10.1002/cmdc.201402032 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/cmdc.201402032 Verlag, lizenzpflichtig, Volltext: https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/cmdc.201402032 
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| Verfasserangaben: | Elke Persch, Steve Bryson, Nickolay K. Todoroff, Christian Eberle, Jonas Thelemann, Natalie Dirdjaja, Marcel Kaiser, Maria Weber, Hassan Derbani, Reto Brun, Gisbert Schneider, Emil F. Pai, R. Luise Krauth-Siegel, and François Diederich |
MARC
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| 520 | |a Abstract The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure-based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small-molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so-called ?mepacrine binding site?. The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T.?cruzi. | ||
| 650 | 4 | |a docking | |
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| 650 | 4 | |a mutation studies | |
| 650 | 4 | |a structure-based design | |
| 650 | 4 | |a trypanothione reductases | |
| 650 | 4 | |a X-ray structures | |
| 700 | 1 | |a Bryson, Steve |e VerfasserIn |4 aut | |
| 700 | 1 | |a Todoroff, Nickolay K. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Eberle, Christian |e VerfasserIn |4 aut | |
| 700 | 1 | |a Thelemann, Jonas |e VerfasserIn |4 aut | |
| 700 | 1 | |a Dirdjaja, Natalie |e VerfasserIn |0 (DE-588)1100399550 |0 (DE-627)859361314 |0 (DE-576)469692405 |4 aut | |
| 700 | 1 | |a Kaiser, Marcel |e VerfasserIn |4 aut | |
| 700 | 1 | |a Weber, Maria |e VerfasserIn |4 aut | |
| 700 | 1 | |a Derbani, Hassan |e VerfasserIn |4 aut | |
| 700 | 1 | |a Brun, Reto |e VerfasserIn |4 aut | |
| 700 | 1 | |a Schneider, Gisbert |e VerfasserIn |4 aut | |
| 700 | 1 | |a Pai, Emil F. |e VerfasserIn |4 aut | |
| 700 | 1 | |a Krauth-Siegel, Renate |e VerfasserIn |0 (DE-588)1050022335 |0 (DE-627)783217390 |0 (DE-576)404300200 |4 aut | |
| 700 | 1 | |a Diederich, François |e VerfasserIn |4 aut | |
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