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Binding to large enzyme pockets : small-molecule inhibitors of trypanothione reductase

Persch, Elke and Bryson, Steve and Todoroff, Nickolay K. and Eberle, Christian and Thelemann, Jonas and Dirdjaja, Natalie and Kaiser, Marcel and Weber, Maria and Derbani, Hassan and Brun, Reto and Schneider, Gisbert and Pai, Emil F. and Krauth-Siegel, R. Luise and Diederich, François. (2014) Binding to large enzyme pockets : small-molecule inhibitors of trypanothione reductase. ChemMedChem, Vol. 9, H. 8. pp. 1880-1891.

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Official URL: http://edoc.unibas.ch/dok/A6289018

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel and Brun, Reto
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Wiley-VCH
ISSN:1860-7179
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:10 Apr 2015 09:14
Deposited On:10 Oct 2014 09:19

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