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 journalArticlepeer-review

Abstract / Description of output

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. 

Original languageEnglish
Pages (from-to)447-454
Number of pages8
JournalEuropean Journal of Medicinal Chemistry
Volume45
Issue number2
DOIs
Publication statusPublished - Feb 2010

Keywords / Materials (for Non-textual outputs)

  • Prostaglandin synthase
  • Docking
  • Structure
  • Inhibition
  • Glutathione transferase

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