Cyclooxygenase-2 - An attractive target for fruitful drug design

Cyclooxygenase, an enzyme involved in the conversion Of C-20 acids to prost aglandins, exists in two isoforms. A third isoform has been recently encoun tered. COX-I is constitutively expressed and has a gastroprotective functio n. COX-2, induced nt the site of injury, is responsible for the expression of pro-inflammatory prostaglandins. Despite overall similarities, COX-I and COX-2 show subtle differences in amino acid composition at the active sire s. COX-2 has valine at positions 89 and 523, while COX-I has isoleucine, re sulting in larger space availability in the former. Further, the presence o f valine at position 434 in COX-2 ns against isoleucine in COX-I allows a g ate mechanism to operate in favour of the former. Molecular modelling studi es 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, dest abilizing and intermolecular energies. A few modified meloxicam derivatives like 19 and 20 are likely to have superior COX-2 selectivity.