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Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D2 synthase

Journal Article


Abstract


  • Prostaglandin D2 synthesised by the hematopoietic prostaglandin D2 synthase has a pro-inflammatory effect in allergic asthma, regulating many hallmark characteristics of the disease. Here we describe identification of hematopoietic prostaglandin D2 synthase inhibitors including cibacron blue, bromosulfophthalein 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.

Authors


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

Publication Date


  • 2010

Citation


  • 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. & Flanagan, J. U. (2010). Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D2 synthase. European Journal of Medicinal Chemistry, 45 (2), 447-454.

Scopus Eid


  • 2-s2.0-73549084724

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/5181

Number Of Pages


  • 7

Start Page


  • 447

End Page


  • 454

Volume


  • 45

Issue


  • 2

Place Of Publication


  • http://www.elsevier.com/wps/find/journaldescription.cws_home/505813/description#description

Abstract


  • Prostaglandin D2 synthesised by the hematopoietic prostaglandin D2 synthase has a pro-inflammatory effect in allergic asthma, regulating many hallmark characteristics of the disease. Here we describe identification of hematopoietic prostaglandin D2 synthase inhibitors including cibacron blue, bromosulfophthalein 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.

Authors


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

Publication Date


  • 2010

Citation


  • 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. & Flanagan, J. U. (2010). Identification and characterisation of new inhibitors for the human hematopoietic prostaglandin D2 synthase. European Journal of Medicinal Chemistry, 45 (2), 447-454.

Scopus Eid


  • 2-s2.0-73549084724

Ro Metadata Url


  • http://ro.uow.edu.au/scipapers/5181

Number Of Pages


  • 7

Start Page


  • 447

End Page


  • 454

Volume


  • 45

Issue


  • 2

Place Of Publication


  • http://www.elsevier.com/wps/find/journaldescription.cws_home/505813/description#description