Identification of indole inhibitors of human hematopoietic prostaglandin D2 synthase (hH-PGDS)
| Autor: | Perry Matthew, Fredrik Edfeldt, Isabella Feierberg, Mattias Rohman, Johan Evenäs, Alison Ward, Jens Petersen, Ulf Sivars, Thomas Hansson, Lisa Wissler, Karin Svensson, Xiao-Hong Zhou, Frank Narjes, Matti Lepistö |
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| Rok vydání: | 2015 |
| Předmět: |
Indoles
Clinical Biochemistry Anti-Inflammatory Agents Pharmaceutical Science Molecular Dynamics Simulation Crystallography X-Ray Biochemistry Structure-Activity Relationship Drug Discovery Humans Potency Transferase Enzyme Inhibitors Molecular Biology Indole test Binding Sites biology Chromogenic Chemistry Organic Chemistry Active site Prostaglandin D2 synthase Hydrogen Bonding Lipocalins Protein Structure Tertiary Intramolecular Oxidoreductases Haematopoiesis biology.protein Molecular Medicine Fluorescence anisotropy Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:2496-2500 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2015.04.065 |
| Popis: | Human H-PGDS has shown promise as a potential target for anti-allergic and anti-inflammatory drugs. Here we describe the discovery of a novel class of indole inhibitors, identified through focused screening of 42,000 compounds and evaluated using a series of hit validation assays that included fluorescence polarization binding, 1D NMR, ITC and chromogenic enzymatic assays. Compounds with low nanomolar potency, favorable physico-chemical properties and inhibitory activity in human mast cells have been identified. In addition, our studies suggest that the active site of hH-PGDS can accommodate larger structural diversity than previously thought, such as the introduction of polar groups in the inner part of the binding pocket. |
| Databáze: | OpenAIRE |
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