Development of a 3D QSAR Model for the Prediction of HDAC2 Inhibitory Activity
Keywords:
HDAC2, HDAC2 inhibitors, 3D QSAR, CoMSIA, Molecular dockingAbstract
Histone Deacetylase 2 (HDAC2) plays an important role in various dangerous disease pathologies such as cancer, and was recently shown to be a desirable target for selective inhibition, thus multiple studies were conducted in an effort to develop potent selective HDAC2 inhibitors. This study focuses on developing a 3D QSAR model using a modified CoMSIA approach, in order to better determine inhibitory activity of novel compounds, while also providing a model to guide further inhibitor design and optimization. The models were generated using 168 carefully selected inhibitors from the literature, and were thereafter evaluated and validated through multiple parameters to determine the model with the best predictivity. The best generated model was then studied to identify important compound physiochemical properties that significantly affect inhibitory activity against HDAC2, and it was found that the presence of large bulky groups at the active site rim, together with an aromatic ring within the hydrophobic channel, enhance HDAC2 inhibitory activity.
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