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Book of Abstracts: Albany 2007

category image Albany 2007
Conversation 15
June 19-23 2007

Computer-Aided, Rational Design of a Potent and Selective Small Peptide Inhibitor of Cyclooxygenase 2 (Cox2)

Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are the mediators of inflammation. This enzyme exists mainly in two isoforms, COX1 and COX2. Prostaglandins responsible for the inflammatory process could be sufficiently controlled with the conventional non-steroidal anti-inflammatory drugs (NSAIDs). These drugs, however, had adverse gastrointestinal side-effects and, therefore, drugs which selectively inhibit COX2, such as the coxibs were developed. Recent reports on the harmful cardiovascular and renal side-effects of the conventional NSAIDs as well as the COX2 selective inhibitors valdecoxib and rofecoxib have once again led to the quest for a novel class of COX2 selective inhibitors.

Keeping this in mind, we have used the available X-ray crystal structures of the complexes of COX1 and COX2 with the known inhibitors to carry out a structure-based, rational, molecular modeling approach to design small peptide inhibitors, which are both potent and selective for COX2. Docking studies using SYBYL 6.81(Tripos Inc) and AutoDock 3.0, indicate that the designed peptides inhibit COX2 with potency in the nanomolar range. Furthermore, they are found to be a thousand-fold selective for COX2 as compared with COX1. Thus, the small peptide inhibitors are suitable lead compounds for the design of a new class of anti-inflammatory drugs.

V Rajakrishnan1, *
V. R. Manoj2
Gita Subba Rao1, **

1Department of Biophysics
All India Institute of Medical Sciences
New Delhi, 110029, India
2Department of Medicine
Saint Vincent Hospital at Worcester Medical Center
Worcester, Massachusetts, USA

*Email: raja_krishnan99@yahoo.co.in
**Email: gitarao@aiims.ac.in