1. Perspective assessment of COX-1 and COX-2 selectivity of nonsteroidal anti-inflammatory drugs from clinical practice: use of genetic function approximation.
- Author
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Zambre AP, Ganure AL, Shinde DB, and Kulkarni VM
- Subjects
- Cyclooxygenase 1 genetics, Cyclooxygenase 2 genetics, Drug Design, Inhibitory Concentration 50, Molecular Structure, Quantitative Structure-Activity Relationship, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cyclooxygenase 1 metabolism, Cyclooxygenase 2 metabolism, Cyclooxygenase Inhibitors chemistry, Cyclooxygenase Inhibitors pharmacology
- Abstract
The beneficial action of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with the inhibition of cyclooxygenase-2 (COX-2), whereas their harmful side effects are associated with the inhibition of COX-1. In order to understand a meaningful comparison of both classical NSAIDs and newer COX-2 drugs, a series of molecules from varied classes of COX-2 inhibitors was studied by the application of three-dimensional quantitative structure-activity relationships (3D-QSAR) using molecular descriptors obtained by genetic function approximation. The features responsible for the dual inhibition of COX-1 and COX-2 and the selective inhibition of COX-2 with factors contributing to the maintenance of optimum selectivity were identified. The QSAR models revealed the importance of thermodynamic, electronic, structural, and molecular shape analysis parameters, which can reasonably modulate the selectivity pattern to avoid unsolicited side effects. An improved understanding to rationalize the COX-1 and COX-2 binding profiles could be gained to develop safe drug design methods.
- Published
- 2007
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