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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. 2011 Oct 13; 54(19):6514-30.JM

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.

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Publisher Full Text
ncbi.nlm.nih.gov
doi.org
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Authors+Show Affiliations

Patterson S
Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, U.K.
Alphey MS
No affiliation info available
Jones DC
No affiliation info available
Shanks EJ
No affiliation info available
Street IP
No affiliation info available
Frearson JA
No affiliation info available
Wyatt PG
No affiliation info available
Gilbert IH
No affiliation info available
Fairlamb AH
No affiliation info available

MeSH

Cell LineCrystallography, X-RayDrug DesignHumansLigandsNADH, NADPH OxidoreductasesProtein BindingProtein ConformationQuinazolinesRecombinant ProteinsStereoisomerismStructure-Activity RelationshipTrypanocidal AgentsTrypanosoma brucei bruceiTrypanosoma cruzi

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21851087

Citation

Patterson, Stephen, et al. "Dihydroquinazolines as a Novel Class of Trypanosoma Brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of Their Binding Mode By Protein Crystallography." Journal of Medicinal Chemistry, vol. 54, no. 19, 2011, pp. 6514-30.
Patterson S, Alphey MS, Jones DC, et al. 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. 2011;54(19):6514-30.
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. (2011). Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: discovery, synthesis, and characterization of their binding mode by protein crystallography. Journal of Medicinal Chemistry, 54(19), 6514-30. https://doi.org/10.1021/jm200312v
Patterson S, et al. 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. 2011 Oct 13;54(19):6514-30. PubMed PMID: 21851087.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: discovery, synthesis, and characterization of their binding mode by protein crystallography. 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, Y1 - 2011/09/01/ PY - 2011/8/20/entrez PY - 2011/8/20/pubmed PY - 2011/12/14/medline SP - 6514 EP - 30 JF - Journal of medicinal chemistry JO - J Med Chem VL - 54 IS - 19 N2 - 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. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/21851087/Dihydroquinazolines_as_a_novel_class_of_Trypanosoma_brucei_trypanothione_reductase_inhibitors:_discovery_synthesis_and_characterization_of_their_binding_mode_by_protein_crystallography_ L2 - https://doi.org/10.1021/jm200312v DB - PRIME DP - Unbound Medicine ER -