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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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Main Authors: Persch, Elke (Author) , Bryson, Steve (Author) , Todoroff, Nickolay K. (Author) , Eberle, Christian (Author) , Thelemann, Jonas (Author) , Dirdjaja, Natalie (Author) , Kaiser, Marcel (Author) , Weber, Maria (Author) , Derbani, Hassan (Author) , Brun, Reto (Author) , Schneider, Gisbert (Author) , Pai, Emil F. (Author) , Krauth-Siegel, Renate (Author) , Diederich, François (Author)
Format: Article (Journal)
Language:English
Published: April 30, 2014
In: ChemMedChem
Year: 2014, Volume: 9, Issue: 8, Pages: 1880-1891
ISSN:1860-7187
DOI:10.1002/cmdc.201402032
Online Access: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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Author Notes: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
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Summary: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.
Item Description:Gesehen am 01.09.2020
Physical Description:Online Resource
ISSN:1860-7187
DOI:10.1002/cmdc.201402032

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