Chemometric rationalization of the structural and physicochemical basis for selective cyclooxygenase-2 inhibition: toward more specific ligands.

The discovery that proinflammatory prostaglandins are produced by cyclooxygenase-2 (COX-2), an inducible isoform of the constitutive cyclooxygenase-1 (COX-1), opened a new frontier in the treatment of inflammatory diseases, because the selective inhibition of COX-2 can lead to therapeutically effective compounds which do not have the common side effects of classical non-steroidal antiinflammatory drugs (NSAIDs). Different crystallographic structures of both free COX-1 and COX-2 as well as complexes with inhibitors have been solved. Because of the great similarity between the two enzymes, it is difficult to detect the most important structural and physicochemical features that would be useful for designing inhibitors with an improved selectivity. In this paper we describe the application of a chemometric procedure to the study of COX-2 selective inhibition. This method, developed to reveal the most suitable regions of isoenzymes for the design of selective ligands, also has a very practical utility. GRID multivariate characterization of the enzymes and subsequent Principal Component Analysis (PCA) of the descriptor variables allow the identification of chemical groups that could be added to a core template structure to increase ligand selectivity.