Structural highlights
Publication Abstract from PubMedThe 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. Binding to Large Enzyme Pockets: Small-Molecule Inhibitors of Trypanothione Reductase.,Persch E, Bryson S, Todoroff NK, Eberle C, Thelemann J, Dirdjaja N, Kaiser M, Weber M, Derbani H, Brun R, Schneider G, Pai EF, Krauth-Siegel RL, Diederich F ChemMedChem. 2014 Apr 30. doi: 10.1002/cmdc.201402032. PMID:24788386[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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This page was last modified 07:20, 14 May 2014.