Cyclooxygenase-2 – an Alluring Target for Meaningful Drug Designing

Cyclooxygenase, an enzyme involved in the conversion of C-20 acids to prostaglandins, exists in two isoforms. 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 difference 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.

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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, rofecoxib, nimesulide meloxicam, nabumetone and etodolac  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.

The revolution in biology over the past two decades has resulted in radically new approaches and opportunities for drug discovery. There has been an incredibly rapid increase in the rate of determination of three-dimensional structures of biomolecules. Many of these macromolecules are important drug targets and it is now possible to use the knowledge of the three-dimensional structures as a good basis for drug design. We propose to illustrate this in the case of cyclooxygenase-2, an enzyme responsible for inflammation.

This area has attracted immense attention in the last few years and a large number of original research articles and a good number of scientific and popular review articles have been published. Aspirin or acetylsalicyclic acid, the prototype of nonsteroidal anti-inflammatory agents (NSAIDs) was first produced and marketed by Bayer in March 1899. NSAIDs are even today among the most widely used therapeutic agents with a total annual sale in excess of US $ 10 billion. They are used for the treatment of a broad spectrum of pathophysiological conditions such as headaches, discomfort associated with minor injuries and alleviation of severe pain caused by inflammatory and degenerative joint diseases such as osteo and rheumatoid arthritis.

The whole 10 pages article is available for download here.