Eurico J. Cabrita

Citation:

Binding of ibuprofen, ketorolac and diclofenac to COX-1 and COX-2 studied by saturation transfer difference NMR, Viegas, Aldino, Manso Joao, Corvo Marta C., Marques Manuel M. B., and Cabrita Eurico J. , Journal of Medicinal Chemistry, Volume 54, Issue 24, p.8555-8562, (2011)

Abstract:

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. Based on this analysis we propose that ketorolac should bind to the COX-2 active site in similar orientation as 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 complement enzyme activity studies in the effort to rationalize COX inhibition mechanisms.

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