Quantitative Structure-Activity Relationship (QSAR) Study of Cyclooxygenase-2 (COX-2) Inhibitors
Junie B. Billones* and Salvador M. Buenaobra
Department of Physical Sciences and Mathematics, and National Institutes of Health, University of the Philippines Manila, Padre Faura St., Ermita, Manila
corresponding author: This email address is being protected from spambots. You need JavaScript enabled to view it.
ABSTRACT
A plethora of selective COX-2 inhibitors belonging to nine chemical classes (pyrrole, imidazole, cyclopentene, benzene, pyrazole, spiroheptene, spiroheptadiene, isoxazole, and thiophene) was subjected to quantitative structure-activity relationship (QSAR) analysis using semi-empirical (AM1)-computed quantum mechanical properties and electrotopological state (E-state) indices. These computed parameters were correlated with experimental inhibitory activities (pIC50). Multilinear regression analyses produced three statistically acceptable models. Model 1 is based on quantum mechanical properties only, Model 2 is an all-E-state relationship, and Model 3 embraces both quantum mechanical and electrotopological parameters. All three models surpassed the commonly allowed minimum predictive squared correlation coefficient (q2) of 0.60. These QSAR results and the probable pharmacophore features identified in this study offer important structural insight into designing novel anti-inflammatory drugs devoid of unwelcome side effects. Guided by the generated models, 18 chemical structures belonging to spiroalkene classes were designed with calculated pIC50 values higher than that of known potent COX-2 inhibitors.
INTRODUCTION
Cyclooxygenase-2 (COX-2) inhibition has been one of the most widely investigated areas of research in the last decade due to its crucial role in relieving pain and other inflammatory conditions. Nonsteroidal anti-inflammatory drugs (NSAIDs) are profoundly used in the treatment of wide variety of inflammatory conditions including osteoarthritis and rheumatoid arthritis (Vane et al. 1996). However, these drugs are associated with high risk of gastrointestinal and renal adverse effects (Allison 1992; DeWitt 1999; Deviere 2002). NSAIDs act by inhibition of cyclooxygenase (COX), the enzyme involved in the biosynthesis of prostaglandins, prostacyclins and thromboxanes from arachidonic acid (Dannhardt 2001; Bleumink 2003). . . . . . . . . . .
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