Investigation On The Possible Inhibitor Effects Of Flavones On The Histone Deacetylase

MOTIVATION: The ability of an organism to respond to its environment resides mainly in its capacity to modulate gene expression program by altering DNA and chromatin structure. Chromatin remodelling by the post-translational modification of histone is a central mechanism for epigenetic regulation of gene expression [Lauffer et al., 2013]. In this context, histone acetyltransferases (HATs) and histone deacetylases (HDACs) are important molecules involved in the regulation of a variety of cellular responses [Lauffer et al., 2013] as well as the dysregulation of their activity has been implicated in a large range of diseases, including cancer, cardiovascular, and neurological diseases. Till now, 18 human HDACs have been identified and classified in four classes. HDAC inhibitors (HDACIs) may constitute a potential therapeutic tool for the treatment of several diseases. They are a class of target anticancer agents, consisting of a diverse group of small molecules like Thichostatin A and vorinostat. HDACIs exert their multiple biological effects by interfering with the cell cycle, inducing apoptosis, autophagy or oxidative stress, and inhibiting angiogenesis [Singh et al., 2015]. Several studies describe different mechanisms of action, but is still not clear the exact mechanism of action of these drugs. Most HDACIs have less specificity to their protein targets; consequently, these can act through nonspecific binding and induce toxic side effects. Therefore, the search for more HDACIs becomes essential as well as essential to determine the exact action mechanism of a drug to make it more specific with no side effects [Singh et al., 2015]. Recent studies suggest that flavones may function as HDACIs [Singh et al., 2015]. Flavones are ubiquitously present in different parts of the plant, including fruits, seed, flower, roots, and leaves [Haberland et al., 2009]. Flavonoids are considered as better chemopreventive molecules because of their daily dietary intake, synergistic effect with other drugs, and less reported toxicity [Singh et al., 2015]. METHODS: In this study, we investigated the possible effect of some flavones molecules on HDAC1 and HADC2 by docking approaches using Autodock 4.2. From PDB database (www.rcsb.org), we selected the best structures of HDAC1 and HDAC2 protein and then we performed the docking between the selected protein structures and the chosen ligands. We applied two types of dockings: hydrated, and not-hydrated, in order to evaluate the functional role of water molecules in the binding sites of the proteins. In both types of dockings, a blind docking was first performed by setting a grid box that included the entire protein surface. In a following step, a focused docking was performed, setting the grid box so that it included only those residues belonging to the binding site of proteins, as it is evident from the PDB file. RESULTS: Our results show that the flavones ligands could interact with the HDAC1 and HDAC2, binding the site that the vorinostat binds on these proteins. Moreover, we think that for some of our ligands, water plays an important role in the interaction. This is in agreement with the current literature. We would like to evaluate these data to understand the specificity of the possible inhibitor effects of the flavones on the HDACs. We believe that the combination of treatments with flavones would be an advantage, and may enhance the effects of the therapy in terms of disease specificity and patient welfare. REFERENCES: [1] B. E. L. Lauffer, R. Mintzer, R. Fong, S. Mukund, C. Tam, I. Zilberleyb, B. Flicke , A. Ritscher, G. Fedorowicz, R. Vallero, D. F. Ortwine, J. Gunzner, Z. Modrusan, L. Neumann, C. M. Koth, P.J. Lupardus, J. S. Kaminker, C. E. Heise, and P. Steiner, Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not Transcription and Cell Viability; The Journal of Biol. Chem. Vol. 288, No.37,Pp.269262694 (2013). [2] P. Singh, R. Singh, T. Srikanta, K. Rath Anticancer potential of the histone deacetylase inhibitor-like effects of flavones, a subclass of polyphenolic compounds: a review; Mol Biol Rep 42:15151531 (2015). [3] Haberland M, Johnson A, Mokalled MH, Montgomery RL, Olson EN, Genetic dissection of histone deacetylase requirement in tumor cells. Proc Natl Acad Sci USA 106 :77517755 (2009).