Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D-2 synthase

Jane E. Weber; Aaron J. Oakley; Angelika N. Christ; Alan G. Clark; John D. Hayes; Rhonda Hall; David A. Hume; Philip G. Board; Mark L. Smythe; Jack U. Flanagan

doi:10.1016/j.ejmech.2009.10.025

Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D-2 synthase

Jane E. Weber, Aaron J. Oakley, Angelika N. Christ, Alan G. Clark, John D. Hayes, Rhonda Hall, David A. Hume, Philip G. Board, Mark L. Smythe, Jack U. Flanagan

Research output: Contribution to journal › Article › peer-review

20 Citations (Scopus)

Abstract

Prostaglandin D-2 synthesised by the hematopoietic prostaglandin D-2 synthase has a pro-inflammatory effect in allergic asthma, regulating many hallmark characteristics of the disease. Here we describe identification of hematopoietic prostaglandin D-2 synthase inhibitors including cibacron blue, bromo-sulfophthalein and ethacrynic acid. Expansion around the drug-like ethacrynic acid identified a novel inhibitor, nocodazole, and a fragment representing its aromatic core. Nocodazole binding was further characterised by docking calculations in combination with conformational strain analysis. The benzyl thiophene core was predicted to be buried in the active site, binding in the putative prostaglandin binding site, and a likely hydrogen bond donor site identified. X-ray crystallographic studies supported the predicted binding mode. (C) 2009 Elsevier Masson SAS. All rights reserved.

Original language	English
Pages (from-to)	447-454
Number of pages	8
Journal	European Journal of Medicinal Chemistry
Volume	45
Issue number	2
DOIs	https://doi.org/10.1016/j.ejmech.2009.10.025
Publication status	Published - Feb 2010

Keywords

Prostaglandin synthase
Docking
Structure
Inhibition
Glutathione transferase
GLUTATHIONE-S-TRANSFERASE
ANTIALLERGIC DRUG HQL-79
CATALYTIC-PROPERTIES
BINDING
INFLAMMATION
CRYSTALLINS
CEPHALOPODS
ACTIVATION
EXPRESSION
MODELS

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10.1016/j.ejmech.2009.10.025

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@article{203f4b684fc043399f59ad811a52c1f1,

title = "Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D-2 synthase",

abstract = "Prostaglandin D-2 synthesised by the hematopoietic prostaglandin D-2 synthase has a pro-inflammatory effect in allergic asthma, regulating many hallmark characteristics of the disease. Here we describe identification of hematopoietic prostaglandin D-2 synthase inhibitors including cibacron blue, bromo-sulfophthalein and ethacrynic acid. Expansion around the drug-like ethacrynic acid identified a novel inhibitor, nocodazole, and a fragment representing its aromatic core. Nocodazole binding was further characterised by docking calculations in combination with conformational strain analysis. The benzyl thiophene core was predicted to be buried in the active site, binding in the putative prostaglandin binding site, and a likely hydrogen bond donor site identified. X-ray crystallographic studies supported the predicted binding mode. (C) 2009 Elsevier Masson SAS. All rights reserved.",

keywords = "Prostaglandin synthase, Docking, Structure, Inhibition, Glutathione transferase, GLUTATHIONE-S-TRANSFERASE, ANTIALLERGIC DRUG HQL-79, CATALYTIC-PROPERTIES, BINDING, INFLAMMATION, CRYSTALLINS, CEPHALOPODS, ACTIVATION, EXPRESSION, MODELS",

author = "Weber, {Jane E.} and Oakley, {Aaron J.} and Christ, {Angelika N.} and Clark, {Alan G.} and Hayes, {John D.} and Rhonda Hall and Hume, {David A.} and Board, {Philip G.} and Smythe, {Mark L.} and Flanagan, {Jack U.}",

year = "2010",

month = feb,

doi = "10.1016/j.ejmech.2009.10.025",

language = "English",

volume = "45",

pages = "447--454",

journal = "European Journal of Medicinal Chemistry",

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T1 - Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D-2 synthase

AU - Weber, Jane E.

AU - Oakley, Aaron J.

AU - Christ, Angelika N.

AU - Clark, Alan G.

AU - Hayes, John D.

AU - Hall, Rhonda

AU - Hume, David A.

AU - Board, Philip G.

AU - Smythe, Mark L.

AU - Flanagan, Jack U.

PY - 2010/2

Y1 - 2010/2

N2 - Prostaglandin D-2 synthesised by the hematopoietic prostaglandin D-2 synthase has a pro-inflammatory effect in allergic asthma, regulating many hallmark characteristics of the disease. Here we describe identification of hematopoietic prostaglandin D-2 synthase inhibitors including cibacron blue, bromo-sulfophthalein and ethacrynic acid. Expansion around the drug-like ethacrynic acid identified a novel inhibitor, nocodazole, and a fragment representing its aromatic core. Nocodazole binding was further characterised by docking calculations in combination with conformational strain analysis. The benzyl thiophene core was predicted to be buried in the active site, binding in the putative prostaglandin binding site, and a likely hydrogen bond donor site identified. X-ray crystallographic studies supported the predicted binding mode. (C) 2009 Elsevier Masson SAS. All rights reserved.

AB - Prostaglandin D-2 synthesised by the hematopoietic prostaglandin D-2 synthase has a pro-inflammatory effect in allergic asthma, regulating many hallmark characteristics of the disease. Here we describe identification of hematopoietic prostaglandin D-2 synthase inhibitors including cibacron blue, bromo-sulfophthalein and ethacrynic acid. Expansion around the drug-like ethacrynic acid identified a novel inhibitor, nocodazole, and a fragment representing its aromatic core. Nocodazole binding was further characterised by docking calculations in combination with conformational strain analysis. The benzyl thiophene core was predicted to be buried in the active site, binding in the putative prostaglandin binding site, and a likely hydrogen bond donor site identified. X-ray crystallographic studies supported the predicted binding mode. (C) 2009 Elsevier Masson SAS. All rights reserved.

KW - Prostaglandin synthase

KW - Docking

KW - Structure

KW - Inhibition

KW - Glutathione transferase

KW - GLUTATHIONE-S-TRANSFERASE

KW - ANTIALLERGIC DRUG HQL-79

KW - CATALYTIC-PROPERTIES

KW - BINDING

KW - INFLAMMATION

KW - CRYSTALLINS

KW - CEPHALOPODS

KW - ACTIVATION

KW - EXPRESSION

KW - MODELS

U2 - 10.1016/j.ejmech.2009.10.025

DO - 10.1016/j.ejmech.2009.10.025

M3 - Article

C2 - 19939518

SN - 0223-5234

VL - 45

SP - 447

EP - 454

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

IS - 2

ER -

Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D-2 synthase

Abstract

Keywords

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