Novel prostaglandin D synthase inhibitors generated by fragment-based drug design.
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.
Hohwy
Morten
M
Global Structural Chemistry and Global Compound Sciences, AstraZeneca Research and Development, S-43183 Mölndal, Sweden.
Spadola
Loredana
L
Lundquist
Britta
B
Hawtin
Paul
P
Dahmén
Jan
J
Groth-Clausen
Ib
I
Nilsson
Ewa
E
Persdotter
Sofia
S
von Wachenfeldt
Karin
K
Folmer
Rutger H A
RH
Edman
Karl
K
D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008024:Ligands; D054834:Lipocalins / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D008970:Molecular Weight; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D008024:Ligands; D054834:Lipocalins; D054852:Small Molecule Libraries; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase