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|2vcq, resolution 1.95Å ()|
|Related:||1v40, 1iyh, 1iyi|
COMPLEX STRUCTURE OF PROSTAGLANDIN D2 SYNTHASE AT 1.95A.
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.
Novel prostaglandin d synthase inhibitors generated by fragment-based drug design., Hohwy M, Spadola L, Lundquist B, Hawtin P, Dahmen J, Groth-Clausen I, Nilsson E, Persdotter S, von Wachenfeldt K, Folmer RH, Edman K, J Med Chem. 2008 Apr 10;51(7):2178-86. Epub 2008 Mar 15. PMID:18341273
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
- Hohwy M, Spadola L, Lundquist B, Hawtin P, Dahmen J, Groth-Clausen I, Nilsson E, Persdotter S, von Wachenfeldt K, Folmer RH, Edman K. Novel prostaglandin d synthase inhibitors generated by fragment-based drug design. J Med Chem. 2008 Apr 10;51(7):2178-86. Epub 2008 Mar 15. PMID:18341273 doi:http://dx.doi.org/10.1021/jm701509k