Abstract

Quantitative structure activity relationship analysis of 41 amide and ester derivatives of indomethacin using Hansch's extra thermodynamic multi-parameter approach and receptor surface analysis has been performed to determine the factors required for selective inhibition of second isoform of cyclooxygenase enzyme by these derivatives. The substrate's conformation was abstracted from Cambridge crystallographic data bank. For the Hansch approach, special emphasis was laid on various electronic, spatial and thermodynamic descriptors at the minimum energy conformation. Receptor surface analysis was performed taking most selective molecule as a reference compound. Statistical analysis was performed using multiple regression analysis for simple quantitative structure activity relationship analysis and genetic function approximation for receptor surface analysis. The quantitative structure activity relationship analysis model derived from receptor surface analysis was found to be significant as compared to those produced from using conventional physico-chemical descriptors. These results provide the tools for predicting the affinity of related compounds and for guiding the design and synthesis of new selective cyclooxygenase-2 inhibitors with predetermined affinity.