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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. June 2006, Volume 5, Number 6, 345-354 |
QSAR Modeling of Sulfonamide Inhibitors of Histone Deacetylase
Divya Jaiswal, Chandrabose Karthikeyan, Sushant Kumar Shrivastava, and Piyush Trivedi
Internet Electron. J. Mol. Des. 2006, 5, 345-354
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Abstract:
Quantitative structure-activity relationships (QSAR) analyses have
been performed on a new set of sulfonamide derivatives applying
linear free energy related (LFER) approach of Hansch to explain
the structural requirements of sulfonamide derivatives for histone
deacetylase inhibition. The lowest energy structures of the
compounds in the series were used to calculate electronic,
thermodynamic and steric parameters available in the molecular
modeling program ChemOffice 2001. Among the various
descriptors studied, energy of highest occupied molecular orbital
(HOMO) and torsion energy (TOE) showed good correlation
(correlation coefficients R = 0.881) with histone deacetylase
inhibitory activity. The best model showed 77.6% explained
variance in the activity with low standard deviation value (0.37)
and a significant F value (36.369). Leave-one-out (LOO) and
leave-25%-out cross-validation was performed to check the
predictive power of the equation, which shows good predictive
ability of the model (q2LOO = 0.711
and q2L25%O = 0.566). The
results of the QSAR study suggest that electron-withdrawing
substituents in the aromatic ring will increase the binding affinity
of sulfonamide derivatives towards histone deacetylase while
bulky substituents are not tolerable for inhibitory activity. The
results obtained from the study can further rationalize the design of
new potent anticancer drug belonging to the category of histone
deacetylase inhibitory sulfonamides.
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