Abstract
Histone deacetylases (HDAC) are metal-dependent enzymes and considered as important targets for cell functioning. Particularly, higher expression of class I HDACs is common in the onset of multiple malignancies which results in deregulation of many target genes involved in cell growth, differentiation and survival. Although substantial attempts have been made to control the irregular functioning of HDACs by employing various inhibitors with high sensitivity towards transformed cells, limited success has been achieved in epigenetic cancer therapy. Here in this study, we used ligand-based pharmacophore and 2-dimensional quantitative structure activity relationship (QSAR) modeling approaches for targeting class I HDAC isoforms. Pharmacophore models were generated by taking into account the known IC50 values and experimental energy scores with extensive validations. The QSAR model having an external R2 value of 0.93 was employed for virtual screening of compound libraries. 10 potential lead compounds (C1-C10) were short-listed having strong binding affinities for HDACs, out of which 2 compounds (C8 and C9) were able to interact with all members of class I HDACs. The potential binding modes of HDAC2 and HDAC8 to C8 were explored through molecular dynamics simulations. Overall, bioactivity and ligand efficiency (binding energy/non-hydrogen atoms) profiles suggested that proposed hits may be more effective inhibitors for cancer therapy.
Highlights
Histone Acetyltransferases (HATs) and Histone deacetylases (HDAC) regulate the acetylation and deacetylation events of small alkaline histones associated with DNA double helical structure [1,2]
In order to select training set compounds, binding affinities, IC50 and molecular descriptors values of known class I HDAC inhibitors were monitored (Tables B, D and E in S1 File). These known hits included MS-275, LBH-589, LAQ-824, Trichostatin A, Saha, Belinostat, Oxamflatin, Pyroxamide, Mocetinostat, and Scriptaid with IC50 values ranging from 5–300 nM. 5–7 pharmacophore models were generated based on the information of docking poses of training set compounds and their pharmacophore fit values were evaluated
Our analysis indicated that backbone root mean square deviation (RMSD) profiles of HDAC2 and HDAC8 systems remained stable during 12 ns molecular dynamics (MD) runs
Summary
Histone Acetyltransferases (HATs) and HDACs regulate the acetylation and deacetylation events of small alkaline histones associated with DNA double helical structure [1,2]. Interactions of positively charged amino-terminal tails of histones with negatively charged phosphodiester backbones of DNA results in chromatin compaction [3,4]. The associated conformational changes which occur due to acetylation of lysine residues result in chromatin remodeling. HATs mediated acetylation promotes chromatin relaxation by loosening the packed histones and DNA, thereby facilitating the accession of transcription factors to bind to respective DNA templates [5,6,7]. Compactness of nucleosome units and controlled gene.
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