Identification of orally bioavailable small-molecule inhibitors of hematopoietic prostaglandin D2 synthase using X-ray fragment based drug discovery

Autor:	Joe Coyle, Lee William Page, Dave Clapham, Karen Affleck, Paul N. Mortenson, Jonathan P. Hutchinson, Ashley Paul Hancock, Melanie Leveridge, Joelle Le, Heather Hobbs, David Norton, Rachel McMenamin, Simon Teague, Emma Sherriff, Linda J. Russell, Sorif Uddin, Caroline Richardson, Anne Cleasby, Simon Teanby Hodgson, Philip J. Day, Martyn Frederickson, Gordon Saxty
Rok vydání:	2014
Předmět:	Pharmacology biology Stereochemistry Chemistry Organic Chemistry Fragment-based lead discovery Pharmaceutical Science Prostaglandin D2 synthase Crystal structure Ligand (biochemistry) Biochemistry Small molecule Protein structure In vivo Drug Discovery biology.protein Molecular Medicine Molecule
Zdroj:	Med. Chem. Commun.. 5:134-141
ISSN:	2040-2511 2040-2503
DOI:	10.1039/c3md00280b
Popis:	Using X-ray crystallographic screening, fragments 4 and 6 were identified as inhibitors of hematopoietic prostaglandin D2 synthase (H-PGDS). Both fragments induced a small protein movement in the X-ray crystal structure relative to the apo structure, where the highly polar nature of the ligand complemented the induced protein conformation. The manuscript describes the fragment optimisation of 4 and 6 followed by fragment growth to lead molecule 10. This showed favourable physicochemical properties and evidence of oral activity in blocking PGD2 generation in vivo.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::3f3850d001e5b02755bbbe21405c11b8 https://doi.org/10.1039/c3md00280b Zobrazit plný text záznamu