Computer-aided design of selective COX-2 inhibitors: comparative molecular field analysis and docking studies of some 3,4-diaryloxazolone derivatives

The recent discovery of a second, inducible isoform of cyclooxygenase, COX-2, has stimulated the search for highly selective non-steroidal anti-inflammatory drugs (NSAIDs). These NSAIDs have the ability to treat pain and inflammation caused by arthritis with less risk of gastrointestinal or renal toxicity. We report here the results of 3D-quantitative structure-activity relationship and docking studies, performed on a series of 3,4-diaryloxazolones. Comparative moleculer field analysis studies provided a good model with cross-validated and conventional r(2) values of 0.688 and 0,969 respectively for 24 analogues in the training set with six components. Docking studies with both COX-1 and COX-2 indicate good selectivity for COX-2. The binding energies between COX-2 and some of the most active oxazolones are comparable to those of celecoxib or rofecoxib. These compounds adopt similar orientations and form similar sets of hydrogen bonds involving the sulfonyl group of the ligand and His 90, Leu 352, Ser 353, Arg 513, Phe 518 and Ser 530 residues of the receptor. Copyright (C) 2001 John Wiley & Sons, Ltd.