Computational characteristics of valproic acid binding to histone deacetylase

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Recently, the antiepileptic drug valproic acid (VPA) has also demonstrated efficacy in the management of cancer and bipolar disorders. These actions are largely mediated by inhibition of the HDAC enzyme/induction of certain genes. Relative to other HDAC inhibitors such as trichostatin-A (TSA), VPA offers higher selectivity on cancer cells with virtually no detrimental effects on normal cells. The molecular underpinnings of these biological profiles for VPA remain undefined. We currently propose for and attempt to identify differences in the binding of VPA and TSA to HDAC. In this paper, conformational changes and energy calculations have been derived. VPA had to accomplish conformational changes in its structure for best accommodation at the HDAC binding site. Energy computations showed that VPA has a lower binding affinity than TSA (-53.80 vs. -66.30 Kcal/mol). These findings demonstrate that VPA binding to HDAC confers catalytic, conformational, and computational characteristics that are distinct from those of TSA. These findings for VPA are consistent with a moderate inhibition of HDAC, a low toxicity on normal cells, and a higher selectivity on cancer cells than TSA. Accordingly, these newly identified binding properties of VPA can state a framework strategy for the rational design of VPA-related anticancer drugs with superior cytodifferentiating- and/or safety-profiles.

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