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

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Molecular Docking Simulations on Histone Deacetylases (HDAC)-1 and -2 to Investigate the Flavone Binding biomedicines Article Molecular Docking Simulations on Histone Deacetylases (HDAC)-1 and -2 to Investigate the Flavone Binding 1, 2, 2 3, Bernardina Scafuri y, Paola Bontempo y , Lucia Altucci , Luigi De Masi * and Angelo Facchiano 4,* 1 Department of Chemistry and Biology “A. Zambelli”, University of Salerno, Via Giovanni Paolo II, 132, Fisciano, 84084 Salerno, Italy; [email protected] 2 Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, via L. De Crecchio 7, 80138 Naples, Italy; [email protected] (P.B.); [email protected] (L.A.) 3 National Research Council (CNR), Institute of Biosciences and BioResources (IBBR), via Università 133, Portici, 80055 Naples, Italy 4 National Research Council (CNR), Institute of Food Science (ISA), via Roma 64, 83100 Avellino, Italy * Correspondence: [email protected] (L.D.M.); [email protected] (A.F.) These authors contributed equally to this research work. y Received: 18 October 2020; Accepted: 2 December 2020; Published: 4 December 2020 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. Keywords: epigenetics; histone deacetylase inhibitors; flavones; molecular simulations 1. 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]. N-terminal tails of histones deacetylated by HDAC have positive charges that interact with the negatively charged phosphate groups of DNA. Consequently, the chromatin is condensed into a compact structure (heterochromatin) associated with low levels of gene transcription. This structural condition can be reversed by HAT activity to a relaxed and transcriptionally active DNA (euchromatin). Therefore, 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]. Biomedicines 2020, 8, 568; doi:10.3390/biomedicines8120568 www.mdpi.com/journal/biomedicines Biomedicines 2020, 8, x 568 FOR PEER REVIEW 22 of of 10 10 To date, 18 eukaryotic HDAC are known and grouped into four classes on the basis of their structuralTo date, and 18 catalytic eukaryotic similarity HDAC [3]. are Class known I with and HDAC1, grouped 2, into3, and four 8 is classes subdivided on the into basis the of three their subclassesstructural andIa (HDAC1 catalytic and similarity 2), Ib (HDAC3), [3]. Class and I with Ic (HDAC8). HDAC1, Class 2, 3, andII is 8formed is subdivided by the two into subclasses the three IIasubclasses (HDAC4, Ia (HDAC1 5, 7, 9) andand 2), IIb Ib (HDAC3),(HDAC6 and Ic10). (HDAC8). Class III Class consists II is formed of NAD by+ the dependent two subclasses HDAC IIa homologous(HDAC4, 5, 7, to 9) the and yeast IIb (HDAC6Sir2 protein and (Sir2-like 10). Class or III sirtuins: consists Sirt1-7). of NAD Class+ dependent IV only HDACincludes homologous HDAC11. Theto the common yeast Sir2 characteristic protein (Sir2-like to classes or sirtuins: I, II, and Sirt1-7). IV is a Classcatalytic IV onlydomain includes with HDAC11.one histidine The (His) common and twocharacteristic aspartate to (Asp) classes residues I, II, and IVassociated is a catalytic with domain Zn2+ withion cofactor one histidine responsible (His) and for two Zn aspartate2+-dependent (Asp) hydrolysisresidues associated of ε-N-acetylated with Zn2+ ion lysine cofactor residues responsible to yield for Zn deacetylated2+-dependent histone hydrolysis by of a" -N-acetylatedcharge-relay mechanismlysine residues [5]. toOverall, yield deacetylated HDACs have histone a conserved by a charge-relay domain belonging mechanism to [5 the]. Overall, open alpha/beta HDACs have fold a class.conserved This domaincentral belongingcore consists to the of openalpha-helices alpha/beta alternating fold class. Thiswith central parallel core beta-strands consists of alpha-helicesthat build a centralalternating beta-sheet. with parallel From here, beta-strands large loops that associate build a central to form beta-sheet. a binding pocket From here, where, large in depth, loops associate the Zn2+ ionto form participates a binding in pocketthe enzyme where, active in depth, site. the Zn2+ ion participates in the enzyme active site. HDAC activityactivity can can be regulatedbe regulated at di ffaterent different levels bylevels transcriptional by transcriptional regulation, regulation, post-translational post- translationalmodifications, modifications, subcellular localization,subcellular localization, protein–protein protein–protein interactions, interactions, proteolytic proteolytic regulation, regulation,and small-molecules and small-molecules acting as HDACacting as inhibitors HDAC inhibitors (HDACi). (HDACi). Thus, HDAC Thus, areHDAC attractive are attractive targets targetsfor the developmentfor the development of novel of drugs, novel and drugs, HDACi and mayHDACi constitute may constitute potential potential therapeutic therapeutic agents. Based agents. on Basedtheir structural on their structural characteristics, characteristics, HDACi of HDACi natural originof natural are subdivided origin are subdivided in hydroxamates, in hydroxamates, benzamides, benzamides,cyclic peptides, cyclic and peptides, short-chain and fattyshort-chain acids [ 2fatty]. Among acids [2]. the Among inhibitors the actinginhibitors on classes acting I-IIon classes HDACs, I- IIthe HDACs, anticancer the anticancer agents Vorinostat agents Vorinostat (suberoylanilide (suberoylanilide hydroxamic hydroxamic acid or SAHA, acid or Figure SAHA,1) Figure and the 1) andstructurally the structurally related Trichostatinrelated Trichostatin A (TSA) A exert (TSA) multiple exert multiple biological biological effectsby effects interfering by interfering with the with cell thecycle, cell inducing cycle, inducing apoptosis, apoptosis, autophagy, autophagy, oxidative oxid stress,ative and stress, inhibiting and angiogenesisinhibiting angiogenesis [6,7]. SAHA [6,7]. and SAHATSA reversibly and TSA bind reversibly to the HDAC bind to active the site,HDAC where active chelate site, thewhere cofactor chelate Zn2 +theby cofactor their hydroxamic Zn2+ by their acid hydroxamicgroup. NAD acid+ dependent group. NAD HDAC+ dependent belonging HDAC to class belonging III (sirtuins) to class are III not (sirtuins) inhibited are bynot conventional inhibited by conventionalHDACi such HDACi as TSA andsuch SAHA as TSA [8 ].and SAHA [8]. Figure 1. Molecular structures of vorinostat, flavone, apigenin, and luteolin are from the PubChem database. FigureA, B, and 1. CMolecular indicate the structures different of rings vorinostat, of flavones. flavone, Images apigenin, are generated and luteolin by DiscoveryStudio4.5. are from the PubChem database. A, B, and C indicate the different rings of flavones. Images are generated by DiscoveryStudio4.5.Since clinically used HDACi still experience adverse effects, to identify novel, more potent and specific inhibitors, plant-derived compounds have been screened and tested against human diseases, includingSince cancers,clinically for used their HDACi ability still to restore experience gene adverse expression effects, alterations to identify [2,6 ,novel,9,10]. Amore previous potent study and specificon the acetonic inhibitors, extract plant-deriv from fruitsed compounds of Feijoa sellowiana have beenO. screened Berg has and identified tested theagainst bioactive human component diseases, including2-phenyl-1,4-benzopyrone cancers, for their (known ability to as restore flavone) gene to show expression anti-cancer alterations action on[2,6 solid,9,10]. and A previous haematological study oncancer the acetonic cells via extract HDAC from inhibition fruits of [9 Feijoa]. This sellowiana natural inhibitor,O. Berg has together identified with the apigenin bioactive and component luteolin, 2-phenyl-1,4-benzopyronebelongs to the subclass of flavonoids (known calledas flavone) flavones andto show is structurally anti-cancer different action from on known solid HDACi. and haematologicalFlavonoids have cancer a backbone cells ofvia 15 HDAC carbon inhibition atoms formed [9]. byThis two natural phenyl inhibitor, rings (A andtogether B) and
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