Investigation of the binding pocket of human hematopoietic prostaglandin (PG) D2 synthase (hH-PGDS): a tale of two waters

Bioorg Med Chem Lett. 2012 Jun 1;22(11):3795-9. doi: 10.1016/j.bmcl.2012.04.004. Epub 2012 Apr 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Allergic Agents / chemical synthesis
  • Anti-Allergic Agents / chemistry*
  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / chemistry*
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Humans
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Intramolecular Oxidoreductases / metabolism
  • Isoquinolines / chemistry
  • Lipocalins / antagonists & inhibitors*
  • Lipocalins / metabolism
  • Naphthalenes / chemistry
  • Protein Structure, Tertiary
  • Water / chemistry*

Substances

  • Anti-Allergic Agents
  • Anti-Inflammatory Agents
  • Enzyme Inhibitors
  • Isoquinolines
  • Lipocalins
  • Naphthalenes
  • Water
  • naphthalene
  • Intramolecular Oxidoreductases
  • prostaglandin R2 D-isomerase
  • isoquinoline

Associated data

  • PDB/4ECO
  • PDB/4EDY
  • PDB/4EDZ
  • PDB/4EEO