2VCQ
Complex structure of prostaglandin D2 synthase at 1.95A.
Summary for 2VCQ
| Entry DOI | 10.2210/pdb2vcq/pdb |
| Related | 1IYH 1IYI 1V40 |
| Descriptor | GLUTATHIONE-REQUIRING PROSTAGLANDIN D SYNTHASE, GLUTATHIONE, 3-phenyl-5-(1H-pyrazol-3-yl)isoxazole, ... (4 entities in total) |
| Functional Keywords | prostaglandin biosynthesis, fatty acid biosynthesis, prostaglandin d2 synthase, pgds, asthma, cytoplasm, isomerase, lipid synthesis |
| Biological source | HOMO SAPIENS (HUMAN) |
| Cellular location | Cytoplasm: O60760 |
| Total number of polymer chains | 4 |
| Total formula weight | 95346.27 |
| Authors | Hohwy, M.,Spadola, L.,Lundquist, B.,von Wachenfeldt, K.,Persdotter, S.,Hawtin, P.,Dahmen, J.,Groth-Clausen, I.,Folmer, R.H.A.,Edman, K. (deposition date: 2007-09-26, release date: 2008-04-15, Last modification date: 2023-12-13) |
| Primary citation | Hohwy, M.,Spadola, L.,Lundquist, B.,Hawtin, P.,Dahmen, J.,Groth-Clausen, I.,Nilsson, E.,Persdotter, S.,Von Wachenfeldt, K.,Folmer, R.H.A.,Edman, K. Novel Prostaglandin D Synthase Inhibitors Generated by Fragment-Based Drug Design. J.Med.Chem., 51:2178-, 2008 Cited by PubMed 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. PubMed: 18341273DOI: 10.1021/JM701509K PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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