Binding to Large Enzyme Pockets: Small‐Molecule Inhibitors of Trypanothione Reductase. Issue 8 (30th April 2014) - Persch, Elke
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.