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

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    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 languageEnglish
    Pages (from-to)447-454
    Number of pages8
    JournalEuropean Journal of Medicinal Chemistry
    Volume45
    Issue number2
    DOIs
    Publication statusPublished - 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

    Cite this

    Weber, J. E., Oakley, A. J., Christ, A. N., Clark, A. G., Hayes, J. D., Hall, R., Hume, D. A., Board, P. G., Smythe, M. L., & Flanagan, J. U. (2010). Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D-2 synthase. European Journal of Medicinal Chemistry, 45(2), 447-454. https://doi.org/10.1016/j.ejmech.2009.10.025