title: Novel prostaglandin D synthase inhibitors generated by fragment-based drug design.
abstract: We describe the discovery of novel inhibitors of prostaglandin D2 synthase (PGDS) through fragment-based lead generation and structure-based drug design. A library of 2500 low-molecular-weight compounds was screened using 2D nuclear magnetic resonance (NMR), leading to the identification of 24 primary hits. Structure determination of protein-ligand complexes with the hits enabled a hit optimization process, whereby we harvested increasingly more potent inhibitors out of our corporate compound collection. Two iterative cycles were carried out, comprising NMR screening, molecular modeling, X-ray crystallography, and in vitro biochemical testing. Six novel high-resolution PGDS complex structures were determined, and 300 hit analogues were tested. This rational drug design procedure culminated in the discovery of 24 compounds with an IC 50 below 1 microM in the in vitro assay. The best inhibitor (IC 50 = 21 nM) is one of the most potent inhibitors of PGDS to date. As such, it may enable new functional in vivo studies of PGDS and the prostaglandin metabolism pathway.
authors.affiliation: Global Structural Chemistry and Global Compound Sciences, AstraZeneca Research and Development, S-43183 Mölndal, Sweden.
authors.forename: Morten
authors.initials: M
authors.lastname: Hohwy
authors.forename: Loredana
authors.initials: L
authors.lastname: Spadola
authors.forename: Britta
authors.initials: B
authors.lastname: Lundquist
authors.forename: Paul
authors.initials: P
authors.lastname: Hawtin
authors.forename: Jan
authors.initials: J
authors.lastname: Dahmén
authors.forename: Ib
authors.initials: I
authors.lastname: Groth-Clausen
authors.forename: Ewa
authors.initials: E
authors.lastname: Nilsson
authors.forename: Sofia
authors.initials: S
authors.lastname: Persdotter
authors.forename: Karin
authors.initials: K
authors.lastname: von Wachenfeldt
authors.forename: Rutger H A
authors.initials: RH
authors.lastname: Folmer
authors.forename: Karl
authors.initials: K
authors.lastname: Edman
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008024:Ligands; D054834:Lipocalins / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D008970:Molecular Weight; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D054834:Lipocalins; D054852:Small Molecule Libraries; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase