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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. April 2006, Volume 5, Number 4, 224-236 |
QSAR Analysis of Indomethacin Derivatives as Selective COX-2 Inhibitors
Hemant Kumar Jain and Ram Kishore Agrawal
Internet Electron. J. Mol. Des. 2006, 5, 224-236
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Abstract:
Selective inhibition of cyclooxygenase-2 (COX-2) is an important
strategy in design of potent anti-inflammatory compounds with
significantly reduced side effects. We selected ester and amide
derivatives of indomethacin to explore the structural requirement
of these analogues necessary for selective COX-2 inhibition. In the
present investigation, a QSAR study was performed using 66 ester
and amide derivatives using Dragon 3.0 structural descriptors.
Cluster analysis technique was applied to generate training and test
sets. The relationship between inhibitory activity and various
descriptors is established by step-wise multiple regression analysis
using SYSTAT 10.2 and VALSTAT. The analyses have produced
good predictive and statistically significant QSAR models. These
models were cross-validated with the leave-one-out (LOO)
method. The values of statistical data are: R = 0.908, F = 37.45,
SEE = 0.317 and R2CV = 0.765
for COX-2 inhibition; R = 0.958, F = 45.00,
SEE = 0.312 and R2CV = 0.836 for COX-1 inhibition; and
R = 0.949, F = 39.7, SEE = 0.392
and R2CV = 0.711 for selectivity.
The predicted activity shows a linear relationship with the
observed activity. The present study suggests that hydrogen
bonding from amide nitrogen to a protein acceptor is an important
determinant of the receptor binding. Lipophilicity and topological
distance indices are important for COX-2 inhibition. Also, the
Geary autocorrelation and eigenvalue descriptors modulate COX-1
and COX-2 inhibition and selectivity. These studies are promising
for the development of novel compounds, which may have potent
anti-inflammatory activity devoid of side effects like gastric ulcer
and renal failures.
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