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

• DOI: 10.1016/j.ejmech.2009.10.025
• Publication Date: 2009-10-24T08:33:08Z
• Authors: 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
• Keywords: Models, Molecular; 0301 basic medicine; Glutathione transferase; Drug Evaluation, Preclinical; Molecular Conformation; Expression; Social and Behavioral Sciences; Docking; GLUTATHIONE-S-TRANSFERASE; ACTIVATION; cibacron blue f3ga; Models; BINDING; Physical Sciences and Mathematics; Keywords: 4 benzhydryloxy 1 [3 (1h tetrazol 5 yl)propyl]piperidine; Enzyme Inhibitors; Inhibition; Glutathione Transferase; 3002 Drug Discovery; Nocodazole; Life Sciences; indometacin; licofelone; Prostaglandin synthase; Lipocalins; 3. Good health; 5 (6 carboxyhexyl) 1 (3 cyclohexyl 3 hydroxypropyl)hydantoin; Intramolecular Oxidoreductases; 3004 Pharmacology; hts 03989; etacrynic acid; ANTIALLERGIC DRUG HQL-79; EXPRESSION; 570; Glutathione-s-transferase; Cephalopods; CRYSTALLINS; MODELS; CATALYTIC-PROPERTIES; 610; Activation; 03 medical and health sciences; INFLAMMATION; Catalytic properties; bromsulfophthalein; Humans; Inflammation; Binding Sites; Antiallergic drug HQL-79; Structure; Binding; Crystallins; Hematopoiesis; diclofenac; jfd 03900; hydrogen; CEPHALOPODS; CMMB; nocodazole Docking; 1605 Organic Chemistry

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, 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.