Histone deacetylases (HDAC) are metal-dependent enzymes and considered as important targets\nfor cell functioning. Particularly, higher expression of class I HDACs is common in the\nonset of multiple malignancies which results in deregulation of many target genes involved in\ncell growth, differentiation and survival. Although substantial attempts have been made to control\nthe irregular functioning of HDACs by employing various inhibitors with high sensitivity\ntowards transformed cells, limited success has been achieved in epigenetic cancer therapy.\nHere in this study, we used ligand-based pharmacophore and 2-dimensional quantitative structure\nactivity relationship (QSAR) modeling approaches for targeting class I HDAC isoforms.\nPharmacophore models were generated by taking into account the known IC50 values and\nexperimental energy scores with extensive validations. The QSAR model having an external\nR2 value of 0.93 was employed for virtual screening of compound libraries. 10 potential lead\ncompounds (C1-C10) were short-listed having strong binding affinities for HDACs, out of which\n2 compounds (C8 and C9) were able to interact with all members of class I HDACs. The potential\nbinding modes of HDAC2 and HDAC8 to C8 were explored through molecular dynamics\nsimulations. Overall, bioactivity and ligand efficiency (binding energy/non-hydrogen atoms)\nprofiles suggested that proposed hits may be more effective inhibitors for cancer therapy.
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