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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. January 2006, Volume 5, Number 1, 13-26 |
Rationalization of Physicochemical Properties of Alkanoic Acid Derivatives
towards Histone Deacetylase Inhibition
Divya Jaiswal, Chandrabose Karthikeyan, and Piyush Trivedi
Internet Electron. J. Mol. Des. 2006, 5, 13-26
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Abstract:
Quantitative Structure-Activity Relationships (QSAR) analyses
have been attempted on a new set of (2-amino-phenyl)-amides of
ω substituted alkanoic acids derivatives using linear free energy
related (LFER) model of Hansch to explain the structural
requirements of derivatives for histone deacetylase inhibition.
The lowest energy structures of the compounds in the series were
used to calculate electronic, thermodynamic, and topological
parameters employing software package ChemOffice 2001. Out
of various descriptors studied, torsion energy (TOE), and sum of
valence degrees (SOVD) showed good correlation with histone
deacetylase inhibitory activity (R = 0.851,
%EV = 72.4, q2 = 0.654)
while dipole moment (DM) and ovality (O) showed good
correlation with activity for induction of histone acetylation in
human bladder T24 cancer cells (R = 0.893,
%EV =79.7, q2 = 0.728).
Sum of valence degrees (SOVD) and radius (R)
contribute to the antiproliferative activity against HCT116 cells
(R = 0.880, %EV = 77.4, q2 = 0.646).
The present study suggests
that bulky substituents in the aromatic ring will decrease the
binding affinity of alkanoic acid derivatives towards histone
deacetylase as indicated by the negative contribution of the
torsion energy. The positive contribution of SOVD illustrates
that increase in branching and presence of heteroatoms is
conducive for antiproliferative activity. The positive correlation
of dipole moment indicates non-covalent, electronic interactions
between the enzyme and inhibitor molecules whereas the
positive correlation of ovality suggests that bulky substituents are
significant for the induction of histone acetylation. Our study
supplements the previous SAR studies and provides the
necessary physico-chemical requirements at the substituents
position for better HDAC inhibitory activity.
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