Binding to large enzyme pockets : small-molecule inhibitors of trypanothione reductase
Date Issued
2014-01-01
Author(s)
Persch, Elke
Bryson, Steve
Todoroff, Nickolay K
Eberle, Christian
Thelemann, Jonas
Dirdjaja, Natalie
Weber, Maria
Derbani, Hassan
Schneider, Gisbert
Pai, Emil F
Krauth-Siegel, R Luise
Diederich, François
DOI
10.1002/cmdc.201402032
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.