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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. August 2007, Volume 6, Number 8, 237-252 |
Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR)
Studies of Various Ether Analogues of Farnesyltransferase
Inhibitors
Tabish Equbal, Om Silakari, and Muttineni Ravikumar
Internet Electron. J. Mol. Des. 2007, 6, 237-252
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Abstract:
The inhibition of farnesyltransferase (FTase) has been vigorously
pursued as a promising target for the treatment of a broad spectrum of
cancers. A set of hundred ether analogues reported as
farnesyltransferase inhibitors (FTIs) were analyzed by employing the
molecular field analysis (MFA) technique to investigate the structural
requirements for various ether analogues to inhibit FTase and to derive
a highly predictive model that may be used for the designing of novel
FTIs. MFA is one of the popular 3D-QSAR methods that relate
biological activity of molecules with steric and electrostatic fields on a
rectangular grid around a bundle of active molecules. MFA studies
were performed with the QSAR module of Cerius2 using genetic
partial least squares (G/PLS) algorithm. The MFA model was
established from the training set of 80 molecules and validated by
predicting the activities of 20 test set molecules. The analysis has
produced statistically significant and reasonably predictive QSAR
model with r = 0.919, r2 = 0.846,
r2cv = 0.785, r2pred = 0.714. The MFA
model was cross-validated with the leave-one-out (LOO) method. The
3D-QSAR models have good correlation and predictive ability. The
model showed that steric (CH3) and electrostatic (H+) interaction play
important role in the inhibition of FTase by ether analogues. The
model generated can be exploited for structural modification in order
to improve FTase inhibition.
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