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.
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