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Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors

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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. / 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 journalArticle

Harvard

Patterson, S, Alphey, MS, Jones, DC, Shanks, EJ, Street, IP, Frearson, JA, Wyatt, PG, Gilbert, IH & Fairlamb, AH 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, vol 54, no. 19, pp. 6514-6530., 10.1021/jm200312v

APA

Patterson, S., Alphey, M. S., Jones, D. C., Shanks, E. J., Street, I. P., Frearson, J. A., ... 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), 6514-6530. 10.1021/jm200312v

Vancouver

Patterson S, Alphey MS, Jones DC, Shanks EJ, Street IP, Frearson JA 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. 2011 Oct 13;54(19):6514-6530. Available from: 10.1021/jm200312v

Author

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. / Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors : Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography.

In: Journal of Medicinal Chemistry, Vol. 54, No. 19, 13.10.2011, p. 6514-6530.

Research output: Contribution to journalArticle

Bibtex - Download

@article{7e5eb18ec1374e5da19aecb5483f10bc,
title = "Dihydroquinazolines as a Novel Class of Trypanosoma brucei Trypanothione Reductase Inhibitors: Discovery, Synthesis, and Characterization of their Binding Mode by Protein Crystallography",
keywords = "ANTIPROTOZOAL ACTIVITIES, GLUTATHIONE-REDUCTASE, ANGSTROM RESOLUTION, CRYSTAL-STRUCTURE, KEY INTERMEDIATE, DRUG DESIGN, IN-VITRO, DERIVATIVES, CRUZI, LEAD",
author = "Stephen Patterson and Alphey, {Magnus S.} and Jones, {Deuan C.} and Shanks, {Emma J.} and Street, {Ian P.} and Frearson, {Julie A.} and Wyatt, {Paul G.} and Gilbert, {Ian H.} and Fairlamb, {Alan H.}",
year = "2011",
doi = "10.1021/jm200312v",
volume = "54",
number = "19",
pages = "6514--6530",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",

}

RIS (suitable for import to EndNote) - Download

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 -

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