Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT

ABSTRACT - Internet Electron. J. Mol. Des. April 2003, Volume 2, Number 4, 242-261

3D-QSAR of Cyclooxygenase-2 Inhibitors by Genetic Function Approximation Anand V. Raichurkar and Vithal M. Kulkarni Internet Electron. J. Mol. Des. 2003, 2, 242-261

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Abstract:
The invention of selective cyclooxygenase-2 (COX-2) inhibitors peaks the first phase of an exciting and fast paced effort to exploit a novel target for nonsteroidal anti-inflammatory drugs (NSAIDs). A series of molecules has been reported as specific COX-2 inhibitors belonging to the class of tetrahydroisoindole nucleus. A 1,3-diaryl substitution on the central polycyclic ring system and absence of sulfonyl moiety are the two structural features of this chemical series. We report the three-dimensional quantitative structure-activity relationship (3D-QSAR) performed by genetic function approximation (GFA) on this class of compounds. QSAR models were generated using a training set of 20 compounds and the predictive ability of each model was assessed using a set of 7 molecules. The internal and external consistency of the final QSAR model was 0.656 and 0.669 respectively. The results indicate that shape (steric), electronic and spatial (conformational) descriptors govern the COX-2 enzyme inhibition. The descriptors appeared in the final model are compatible with the COX-2 enzyme topology. A hypothetical mechanism of enzyme-inhibitor interaction was derived to gain important structural insights into designing novel antiinflammatory agents prior to their synthesis.

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