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

European Journal of Medicinal Chemistry
Jane E WeberJack U Flanagan

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, 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.

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Citations

Mar 25, 2011·Drug Metabolism Reviews·Aaron Oakley
Mar 24, 2011·Drug Metabolism Reviews·Jack U Flanagan, Mark L Smythe
Nov 6, 2012·Trends in Pharmacological Sciences·Baojian Wu, Dong Dong
Oct 21, 2015·Journal of Chemical Information and Modeling·Rosa BuonfiglioThierry Kogej
Jul 14, 2012·Mediators of Inflammation·Myungsoo Joo, Ruxana T Sadikot
Jan 17, 2020·Critical Reviews in Toxicology·Patrick E Hanna, M W Anders
Jun 21, 2011·Immunological Reviews·Nirav R Bhakta, Prescott G Woodruff

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