2VCZ: Complex Structure Of Prostaglandin D2 Synthase At 1.95a

Citation:
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.
PDB ID: 2VCZDownload
MMDB ID: 63792
PDB Deposition Date: 2007/9/28
Updated in MMDB: 2012/10
Experimental Method:
x-ray diffraction
Resolution: 1.95  Å
Source Organism:
Similar Structures:
Biological Unit for 2VCZ: dimeric; determined by author and by software (PQS)
Molecular Components in 2VCZ
Label Count Molecule
Proteins (2 molecules)
2
Glutathione-requiring Prostaglandin D Synthase(Gene symbol: HPGDS)
Molecule annotation
Chemicals (3 molecules)
1
2
2
1
* Click molecule labels to explore molecular sequence information.

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