Binding to large enzyme pockets: small-molecule inhibitors of trypanothione reductase.
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.
Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093 Zurich (Switzerland).
Elke
E
Persch
Steve
S
Bryson
Nickolay K
NK
Todoroff
Christian
C
Eberle
Jonas
J
Thelemann
Natalie
N
Dirdjaja
Marcel
M
Kaiser
Maria
M
Weber
Hassan
H
Derbani
Reto
R
Brun
Gisbert
G
Schneider
Emil F
EF
Pai
R Luise
RL
Krauth-Siegel
François
F
Diederich
D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D056004:Molecular Dynamics Simulation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000201:enzymology
D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D015800:Protozoan Proteins; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase
X-ray structures; docking; inhibitors; mutation studies; structure-based design; trypanothione reductases