Download MendeleyNovel 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, R.H.A., Edman, K.(2008) J Med Chem 51: 2178
- PubMed: 18341273
- DOI: https://doi.org/10.1021/jm701509k
- Primary Citation of Related Structures:
2VCQ, 2VCW, 2VCX, 2VCZ, 2VD0, 2VD1 - 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.
Organizational Affiliation:
Global Structural Chemistry and Global Compound Sciences, AstraZeneca Research and Development, S-43183 M?lndal, Sweden.
