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J Med Chem. 2011 Dec 22;54(24):8555-62. doi: 10.1021/jm201090k. Epub 2011 Nov 29.

Binding of ibuprofen, ketorolac, and diclofenac to COX-1 and COX-2 studied by saturation transfer difference NMR.

Author information

1
Departamento de Química, Faculdade de Ciências e Tecnologia-UNL, REQUIMTE, CQFB, 2829-516 Caparica, Portugal.

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. 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.

PMID:
22091869
DOI:
10.1021/jm201090k
[Indexed for MEDLINE]

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