QSAR study on aminophenylbenzamides and acrylamides as histone deacetylase inhibitors: An insight into the structural basis of antiproliferative activity

Abstract

Histone deacetylases have emerged as important drug target with a multitude of therapeutic potentials for their inhibitors. With the purpose of designing new chemical entities with enhanced inhibitory potencies against histone deacetylases, a two-dimensional (2D) quantitative structure-activity relationship (QSAR) study was carried out on aminophenylbenzamides and acrylamide derivatives as inhibitors of these deacetylases. The developed model was validated by standard QSAR parameters and through a detailed structural analysis of how it reproduces and explains the differences in the experimentally known activity data. The model showed a good correlative and predictive ability, with a cross-validated correlation coefficient of 0.594. The conventional and predictive correlation coefficients were found to be 0.725 and 0.577 for the antiproliferative activity of aminophenylbenzamides and acrylamide series, respectively. The study indicated that their antiproliferative activity is largely explained by the steric factors of the substituents, highlighting the role of the size and shape of the inhibitor in forming effective binding interactions with histone deacetylase. The models could be usefully employed to design inhibitors with greatly enhanced potency and selectivity.

Rational Drug Design of Antineoplastic Agents Using 3D-QSAR, Cheminformatic, and Virtual Screening Approaches

“…Both 2D-and 3D-QSAR approaches have been very useful in the design of novel HDAC inhibitors with enhanced potency and isoform selectivity. The developed QSAR models were employed to identify HDAC pharmacophores, optimize HDAC inhibitors and evaluate the inhibitory potency of the novel designed inhibitors [7,66,67]. The CoMFA and CoMSIA 3D-QSAR methodology has been used for development of novel HDAC inhibitors [68][69][70][71][72].…”

Computational Epigenetics: the new scientific paradigm

“…These algorithms allow the screening of histone marks in large sets of protein sequences, such as those encoded by the complete genomes of higher complexity organisms. In recent years, a number of structure-based techniques, including quantitative structure-activity relationship (QSAR) analysis [99], [100], homology modeling [101] and molecular docking techniques [102], for the design of epigenetic inhibitors were also described. Dynamic activities over the past two years have seen the development of at least five computational methods for the functional annotation of epigenetic factors [96], [103].…”

Quantitative structure activity relationship (QSAR) of N 6-substituted adenosine receptor agonists as potential antihypertensive agents

“…It automatically calculates numerical descriptors of molecular structures and employs statistics to obtain a correlation. The calculated descriptors included molecular attributes, molecular indices, atom counts, and VAMP parameters (Cronin and Schultz, 2001;Dessalew, 2007). The TSAR methodology assumes that a suitable sampling of these structural descriptors provides all the information needed for understanding their biological properties (Klocker et al, 2002;Kovatcheva et al, 2003).…”