The aspirin binding site:
comparison of COX-1 and COX-2
Nonsteroidal anti-inflammatory drugs, such as aspirin, work by inhibiting
the enzyme cyclooxygenase-2 (COX-2, shown in green). Aspirin,
however can also bind to and inhibit a similar enzyme, cyclooxygenase-1
(COX-1, shown in blue), causing stomach irritation and bleeding.
The figures on the left are slices of molecular models of the two enzymes
that show how aspirin (orange) binds to each of them, fitting easily into
the interior of each molecule. The structural similarity of the two
enzymes is apparent from the views. Recently, the FDA has approved
celecoxib, a much more selective inhibitor of COX-2 with little affinity
for COX-1. The figures on the right show how celecoxib (maroon) binds
to COX-2 as well as aspirin does, but fails to bind to COX-1 because it
does not fit in the available space.
The previous
image shows a different view of COX-2 and celecoxib, together with
a new, modified form of the drug that has an even higher calculated affinity
for COX-2. (Celecoxib is shown in maroon with the modifications added
in blue.) The modified form of celecoxib was designed and tested
computationally by Hibiki Kawamata ('99), an undergraduate student at Smith
College. The molecular modeling was part of the Pharmacology course
(CHM 357b, spring 1999), and was performed using equipment and software
(QUANTA) obtained through a Howard Hughes Medical Institute grant.
This page was created on May 18th 1999
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