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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. February 2009, Volume 8, Number 2, 14-28 |
Design of New Chemicals Entities as Selective COX-2 Inhibitors
using Structure Optimization by Molecular Modeling Studies
Shashikant Bhandari, Kailash Bothara, Vidya Pawar, Deepak Lokwani, and Titiksh Devale
Internet Electron. J. Mol. Des. 2009, 8, 14-28
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Abstract:
The quest for design of selective nontoxic anti-inflammatory analgesic agent
is continuously going on since more than last 30 years. Keeping the same objective
in mind as an attempt to develop potent and nontoxic, nonsteroidal analgesic
anti-inflammatory agents, we have optimized the diaryl pharmacophore by using
molecular modeling studies. In this paper we present results of 2D and 3D QSAR
studies of series of 80 molecules containing 4,5-diarylimidazole pharmacophore as
selective cyclooxygenase-2 (COX-2) inhibitors. The 3D QSAR studies were performed
using two different methods, stepwise variable selection
k-nearest neighbor molecular
field analysis (SW kNN-MFA) and simulated annealing
k-nearest neighbor molecular
field analysis (SA kNN-MFA) methods. The 2D QSAR studies were performed using
multiple regression. 3D QSAR studies produced reasonably good predictive models
with high cross-validated r2cv value of 0.688 and 0.733
and conventional r2 value of 0.912 and 0.794 values using the models
SW kNN-MFA and SA kNN-MFA method respectively,
whereas the r2 value in 2D QSAR studies was found to be 0.8943.
The output of present research work is interesting, the 2D QSAR studies
indicated contribution of different physicochemical descriptors and
the result of 3D QSAR studies indicated the exact steric and electronic
requirement in the ranges at various positions around 4,5-diaryl imidazole
pharmacophore. Thus the pharmacophore requirement for selective COX-2
inhibition was optimized and requirement at various positions around
4,5-diaryl imidazole pharmacophore were defined.
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