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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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