Perspective Assessment of COX-1 and COX-2 Selectivity of Nonsteroidal Anti-Inflammatory Drugs from Clinical Practice: Use of Genetic Function Approximation

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• 作者：Ajit P. Zambre ; Ashok L. Ganure ; Devanand B. Shinde ; Vithal M. Kulkarni
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2007
• 出版时间：March 2007
• 年：2007
• 卷：47
• 期：2
• 页码：635 - 643
• 全文大小：119K
• 年卷期：v.47,no.2(March 2007)
• ISSN：1549-960X

文摘

The beneficial action of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with the inhibition ofcyclooxygenase-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, aseries of molecules from varied classes of COX-2 inhibitors was studied by the application ofthree-dimensional quantitative structure-activity relationships (3D-QSAR) using molecular descriptorsobtained by genetic function approximation. The features responsible for the dual inhibition of COX-1 andCOX-2 and the selective inhibition of COX-2 with factors contributing to the maintenance of optimumselectivity were identified. The QSAR models revealed the importance of thermodynamic, electronic,structural, and molecular shape analysis parameters, which can reasonably modulate the selectivity patternto avoid unsolicited side effects. An improved understanding to rationalize the COX-1 and COX-2 bindingprofiles could be gained to develop safe drug design methods.