2WPF

Trypanosoma brucei trypanothione reductase in complex with 3,4- dihydroquinazoline inhibitor (DDD00085762)

Summary for 2WPF

• Entry DOI: 10.2210/pdb2wpf/pdb
• Related: 2WOI 2WOV 2WOW 2WP5 2WP6 2WPC 2WPE
• Descriptor: TRYPANOTHIONE REDUCTASE, FLAVIN-ADENINE DINUCLEOTIDE, 3-[(4S)-6-CHLORO-2-METHYL-4-(4-METHYLPHENYL)QUINAZOLIN-3(4H)-YL]-N,N-DIMETHYLPROPAN-1-AMINE, ... (6 entities in total)
• Functional Keywords: oxidoreductase, trypanosomiasis, sleeping sickness, flavoprotein, redox-active center
• Biological source: TRYPANOSOMA BRUCEI
• Cellular location: Cytoplasm: P39051
• Total number of polymer chains: 4
• Total formula weight: 219045.58

Authors

Alphey, M.S.,Patterson, S.,Fairlamb, A.H. (deposition date: 2009-08-06, release date: 2010-10-13, Last modification date: 2024-11-13)

Primary citation

Patterson, S.,Alphey, M.S.,Jones, D.C.,Shanks, E.J.,Street, I.P.,Frearson, J.A.,Wyatt, P.G.,Gilbert, I.H.,Fairlamb, A.H.
Dihydroquinazolines as a Novel Class of Trypanosoma Brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of Their Binding Mode by Protein Crystallography.
J.Med.Chem., 54:6514-, 2011

PubMed Abstract: Trypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei , the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay.

PubMed: 21851087
DOI: 10.1021/JM200312V

Experimental method

X-RAY DIFFRACTION (1.9 Å)