%0 Journal Article %J J Med Chem %D 2011 %T Binding of ibuprofen, ketorolac, and diclofenac to COX-1 and COX-2 studied by saturation transfer difference NMR %A A. Viegas %A Manso, J. %A Corvo, Mc %A M.M. Marques %A E. J. Cabrita %K Animals Binding %K Competitive Catalytic Domain Cyclooxygenase 1/*chemistry Cyclooxygenase 2/*chemistry Cyclooxygenase Inhibitors/*chemistry Diclofenac/*chemistry Female Ibuprofen/*chemistry Ketorolac/*chemistry Magnetic Resonance Spectroscopy Male Sheep %P 8555-62 %R 10.1021/jm201090k %U http://www.ncbi.nlm.nih.gov/pubmed/22091869 %V 54 %X

Saturation transfer difference NMR (STD-NMR) spectroscopy has emerged as a powerful screening tool and a straightforward way to study the binding epitopes of active compounds in early stage lead discovery in pharmaceutical research. Here we report the application of STD-NMR to characterize the binding of the anti-inflammatory drugs ibuprofen, diclofenac, and ketorolac to COX-1 and COX-2. Using well-studied COX inhibitors and by comparing STD signals with crystallographic structures, we show that there is a relation between the orientations of ibuprofen and diclofenac in the COX-2 active site and the relative STD responses detected in the NMR experiments. On the basis of this analysis, we propose that ketorolac should bind to the COX-2 active site in an orientation similar to that of diclofenac. We also show that the combination of STD-NMR with competition experiments constitutes a valuable tool to address the recently proposed behavior of COX-2 as functional heterodimers and complements enzyme activity studies in the effort to rationalize COX inhibition mechanisms.

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