PDBsum entry 2vcq

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Isomerase PDB id
Protein chain
198 a.a.
GSH ×4
D25 ×3
Waters ×363

References listed in PDB file
Key reference
Title Novel prostaglandin d synthase inhibitors generated by fragment-Based drug design.
Authors M.Hohwy, L.Spadola, B.Lundquist, P.Hawtin, J.Dahmen, I.Groth-Clausen, E.Nilsson, S.Persdotter, K.Von wachenfeldt, R.H.A.Folmer, K.Edman.
Ref. J.Med.Chem., 2008, 51, 2178. [DOI no: 10.1021/jm701509k]
PubMed id 18341273
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.
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