title: Investigation of the binding pocket of human hematopoietic prostaglandin (PG) D2 synthase (hH-PGDS): a tale of two waters.
abstract: The inhibition of hH-PGDS has been proposed as a potential target for the development of anti-allergic and anti-inflammatory drugs. Herein we describe our investigation of the binding pocket of this important enzyme and our observation that two water molecules bind to our inhibitors and the enzyme. A series of compounds were prepared to the probe the importance of the water molecules in determining the binding affinity of the inhibitors to the enzyme. The study provides insight into the binding requirements for the design of potent hH-PGDS inhibitors.
authors.affiliation: Departments of Medicinal Chemistry, Pfizer Global Research and Development, Chesterfield, MO 63017, United States. john.i.trujillo@pfizer.com
authors.forename: John I
authors.initials: JI
authors.lastname: Trujillo
authors.forename: James R
authors.initials: JR
authors.lastname: Kiefer
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Day
authors.forename: Joseph
authors.initials: J
authors.lastname: Moon
authors.forename: Gina M
authors.initials: GM
authors.lastname: Jerome
authors.forename: Christine P
authors.initials: CP
authors.lastname: Bono
authors.forename: Christine M
authors.initials: CM
authors.lastname: Kornmeier
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Williams
authors.forename: Cyrille
authors.initials: C
authors.lastname: Kuhn
authors.forename: Glen R
authors.initials: GR
authors.lastname: Rennie
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wynn
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Carron
authors.forename: Atli
authors.initials: A
authors.lastname: Thorarensen
mesh_terms: D018926:Anti-Allergic Agents / Q000138:chemical synthesis / Q000737:chemistry*; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007546:Isoquinolines / Q000737:chemistry; D054834:Lipocalins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009281:Naphthalenes / Q000737:chemistry; D017434:Protein Structure, Tertiary; D014867:Water / Q000737:chemistry*
chemical_list: D018926:Anti-Allergic Agents; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D054834:Lipocalins; D009281:Naphthalenes; D014867:Water; C031721:naphthalene; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; C039109:isoquinoline