Exploring structural requirements of isoform selective histone deacetylase inhibitors: a comparative in silico study

Histone deacetylases (HDACs) are a widely popular class of epigenetic regulators, second only in importance to DNA methyltransferases. They are responsible for deacetylating the lysine residues of a wide range of proteins, both nuclear and cytoplasmic. Therefore, deregulated HDAC activity is implicated in disruption of important biological functions leading to cancerous, neuropathological, infectious and inflammatory diseased states. The current therapeutic strategies aimed at combating HDAC related pathologies consist of pan HDAC inhibitors that target multiple HDAC isoforms. Many side-effects of such therapeutics have been reported due to off-target effects. Hence, efforts need to be focused towards developing therapeutics targeting single isoforms. This work aims at recognizing structural features, both of receptors and inhibitors, that would help achieve selective inhibition of HDAC isoforms. Protein alignment studies have been carried out to define the receptor structure differences that can be exploited for this purpose. Binding modes of highly isoform selective inhibitors have been established through molecular docking studies to characterize the receptor-ligand interactions responsible for selective inhibition. This information is represented with the help of pharmacophore models.