Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors : Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography. / Patterson, Stephen; Alphey, Magnus S.; Jones, Deuan C.; Shanks, Emma J.; Street, Ian P.; Frearson, Julie A.; Wyatt, Paul G.; Gilbert, Ian H.; Fairlamb, Alan H.
In: Journal of Medicinal Chemistry, Vol. 54, No. 19, 13.10.2011, p. 6514-6530.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors
T2 - Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography
A1 - Patterson,Stephen
A1 - Alphey,Magnus S.
A1 - Jones,Deuan C.
A1 - Shanks,Emma J.
A1 - Street,Ian P.
A1 - Frearson,Julie A.
A1 - Wyatt,Paul G.
A1 - Gilbert,Ian H.
A1 - Fairlamb,Alan H.
AU - Patterson,Stephen
AU - Alphey,Magnus S.
AU - Jones,Deuan C.
AU - Shanks,Emma J.
AU - Street,Ian P.
AU - Frearson,Julie A.
AU - Wyatt,Paul G.
AU - Gilbert,Ian H.
AU - Fairlamb,Alan H.
PY - 2011/10/13
Y1 - 2011/10/13
N2 - <p>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.</p>
AB - <p>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.</p>
KW - ANTIPROTOZOAL ACTIVITIES
KW - GLUTATHIONE-REDUCTASE
KW - ANGSTROM RESOLUTION
KW - CRYSTAL-STRUCTURE
KW - KEY INTERMEDIATE
KW - DRUG DESIGN
KW - IN-VITRO
KW - DERIVATIVES
KW - CRUZI
KW - LEAD
U2 - 10.1021/jm200312v
DO - 10.1021/jm200312v
M1 - Article
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 19
VL - 54
SP - 6514
EP - 6530
ER -