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 cyclooxyg enase-2 (COX-2), an inducible isoform of the constitutive cyclooxygenase-1 (COX-1), opened a new frontier in the treatment of inflammatory diseases, b ecause the selective inhibition of COX-2 can lead to therapeutically effect ive compounds which do not have the common side effects of classical non-st eroidal antiinflammatory drugs (NSAIDs). Different crystallographic structu res 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 feat ures that would be useful for designing inhibitors with an improved selecti vity. In this paper we describe the application of a chemometric procedure to the study of COX-2 selective inhibition. This method, developed to revea l the most suitable regions of isoenzymes for the design of selective ligan ds, also has a very practical utility. GRID multivariate characterization o f the enzymes and subsequent Principal Component Analysis (PCA) of the desc riptor variables allow the identification of chemical groups that could be added to a core template structure to increase ligand selectivity.