Cyclooxygenase-2: an attractive target for fruitful drug design

Abstract

Cyclooxygenase, an enzyme involved in the conversion of C-20 acids to prostaglandins, exists in two isoforms. A third isoform has been recently encountered. COX-1 is constitutively expressed and has a gastroprotective function. COX-2, induced at the site of injury, is responsible for the expression of pro-inflammatory prostaglandins. Despite overall similarities, COX-1 and COX-2 show subtle differences in amino acid composition at the active sites. COX-2 has valine at positions 89 and 523, while COX-1 has isoleucine, resulting in larger space availability in the former. Further, the presence of valine at position 434 in COX-2 as against isoleucine in COX-1 allows a gate mechanism to operate in favour of the former. Molecular modelling studies explain the preferential COX-2 inhibitory activity of some nonsteroidal anti-inflammatory agents like celecoxib (3), rofecoxib (4), nimesulide (5), meloxicam (6), nabumetone (10) and etodolac (13) in terms of binding, destabilizing and intermolecular energies. A few modified meloxicam derivatives like 19 and 20 are likely to have superior COX-2 selectivity.