Quantitative Structure-Activity Relationship and Molecular Modeling Studies on a Series of Hydroxamate Analogues Acting as HDAC Inhibitors
DOI:
https://doi.org/10.12970/2308-8044.2014.02.02.1Keywords:
Hydroxamate analogues, Histone deacetylase inhibitors, Molecular modeling, Quantitative structure-activity relationship.Abstract
In this communication, a quantitative structure-activity relationship (QSAR) study has been performed on a series of trichostatin A (TSA) and suberanilo hydroxamic acid (SAHA) analogues acting as histone deacetylase (HDAC1) inhibitors to investigate their physicochemical properties that govern their activity. In this study, a significant 2D QSAR model was obtained correlating the activity of the compounds with their parachor and some indicator variables which suggested that molecules may have dispersion interaction with the receptor and that their surface tension may greatly help to this interaction. Further, the indicator parameters suggested that SO2NH moiety present in the molecule may not be conducive to the activity, but the straight chain joining the aromatic rings with hydroxamate moiety and having ≥6 single bonds may be favorable to the activity, provided it has no substituent at any carbon. Using the model, some new compounds in the series have been predicted and docked to see their interaction with the HDAC1. All compounds have been found to have better interaction with the enzyme than TSA and SAHA, the two FDA approved HDAC inhibitors, and all the compounds obey Lipinski’s rule of 5.
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