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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. October 2007, Volume 6, Number 10, 320-330 |
3D-QSAR CoMFA Study on Human Glutaminyl Cyclase Inhibitors
Munuganti Ravi Shashi Nayana, Yadavalli Nataraja Sekhar, Nunna Siva Kumari, and Shaik Mahmood
Internet Electron. J. Mol. Des. 2007, 6, 320-330
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Abstract:
Glutaminyl cyclase (QC), besides its crucial role in hormone maturation
and its pathophysiological involvement in Alzheimer's disease, is a new
potential drug target. To understand the structural requirements of QC
ligands and to design new ligands against human glutaminyl cyclase with
enhanced inhibitory potency we performed a 3D-QSAR (quantitative
structure-activity relationships) study with comparative molecular field
analysis (CoMFA) for a dataset of 50 imidazole derivatives which are
inhibitors of human glutaminyl cyclase. Comparative molecular field
analysis (CoMFA) QSAR models were computed with Sybyl 6.7v. The
3D-QSAR model has very good statistics, namely leave-one-out (LOO)
cross-validated correlation coefficient q2 = 0.647, non-cross-validated
correlation coefficient r2 = 0.917, and the predicted correlation coefficient
r2pred = 0.652.
Based on the high values for q2 and r2 we are confident that
the 3D-QSAR model gives good predictions that may be used to design
better QC inhibitors. The CoMFA model reveals the most significant
correlation of steric and electrostatic fields with biological activities. The
information derived from this study provides a tool for guiding further
structural modification to obtain more potent inhibitors of QC.
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