Molecular Docking Simulations on Histone Deacetylases (HDAC)-1 and -2 to Investigate the Flavone Binding.

Bernardina Scafuri,Lucia Altucci,Luigi De Masi,Paola Bontempo,Angelo Facchiano

doi:10.3390/biomedicines8120568

Abstract

Histone modifications through acetylation are fundamental for remodelling chromatin and consequently activating gene expression. The imbalance between acetylation and deacetylation activity causes transcriptional dysregulation associated with several disorders. Flavones, small molecules of plant origin, are known to interfere with class I histone deacetylase (HDAC) enzymes and to enhance acetylation, restoring cell homeostasis. To investigate the possible physical interactions of flavones on human HDAC1 and 2, we carried out in silico molecular docking simulations. Our data have revealed how flavone, and other two flavones previously investigated, i.e., apigenin and luteolin, can interact as ligands with HDAC1 and 2 at the active site binding pocket. Regulation of HDAC activity by dietary flavones could have important implications in developing epigenetic therapy to regulate the cell gene expression.

Highlights

The fine remodelling of the chromatin structure by post-translational covalent modifications of histone tails is a key mechanism for epigenetic regulation of gene expression [1,2]
The levels of histone acetylation are the result of the HAT/histone deacetylase (HDAC) activity balance that plays a crucial role in the regulation of gene transcription through modulation of epigenetic changes
Docking simulations were performed between the two enzymes and vorinostat, flavone, apigenin, and luteolin, with AutoDock 4.2 and AutoDockTools4 [16], to verify the suitability of the molecular structure of flavone, apigenin, and luteolin to interact with HDAC1 and HDAC2 at the same binding site occupied by vorinostat

Summary

Introduction

The fine remodelling of the chromatin structure by post-translational covalent modifications (acetylation, methylation, phosphorylation, and clipping) of histone tails is a key mechanism for epigenetic regulation of gene expression [1,2]. In this context, histone acetyltransferases (EC 2.3.1.48, HAT) and histone deacetylases (EC 3.5.1.98, HDAC) are essential enzymes in adding and removing, respectively, the acetyl moiety on the amino acid lysine [1]. The levels of histone acetylation are the result of the HAT/HDAC activity balance that plays a crucial role in the regulation of gene transcription through modulation of epigenetic changes. Alterations of this tightly coordinated molecular system have been implicated in a range of diseases including inflammation, cardiovascular and neurodegenerative disorders, diabetes, and cancer [3,4]

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