1. INTRODUCTION:

The hereditary unit of information, Deoxyribonucleic Acid (DNA) is present as compact structure chromatin, with the help of the histone and non-histone proteins. Combination of various Post-Translational Modification, such as, Methylation, Ubiquitylation, Phosphorylation, Sumoylation etc, is an analytic method of transcriptional activation of the gene. Among which, acetylation is the most important one, resulting in chromosomal structural modification prominent to nucleosomal relaxation, thus triggering transcriptional activation and the transcription repression occur due the deacetylation. The equilibrium between the acetylation and deacetylation of the histone and non-histone proteins is essential for the regulation of the transcription and is controlled by the Histone Acetyltransferase (HAT) and Histone Deacteylase (HDAC) respectively [2] [22].

Imbalance of such leads to abnormal gene expression, even causing cancer development. Meanwhile HAT adds acetyl group to the e amino group of the lysine residue, counterbalancing the positive charge, thus facilitating the transcription factor (T_f) to fix to the nucleosomal DNA and increasing the transcription, HDAC catalyzes the cleavage of the L-lysine side chain to L-lysine and acetate, compacting the chromatin, restricting the T_f thus repressing the gene expression [11]. HDACs are involved in the initiation of the depression, proven in vitro, after the study that investigated the anti-depressive effects of Gami-Shinkiwhan in mice [33]. The result showed the decrease in the level of the caspase-3 and HDAC3, upon the induction of the medicine. Being regulated by various external and internal factors, such as the decrease in the expression of HDAC with the presence the cigarette smoke via transcription of inflammatory gene [43]

1.1 Classes and localization:

The two human protein families exhibit the HDAC activity; classical and SIR2 HDAC family that differ in their catalytic mechanism. The former has three phylogenetic members: HDAC class I and class II and class IV, while the latter has HDAC class III. Class I consist of HDAC1, HDAC2, HDAC3 and HDAC8, which are expressed more in different cell lines in comparison to the class II, HDAC4, HDAC5, HDAC6, HDAC7, HDAC9. The classical HDAC are Zn²⁺ dependent enzymes, containing the Zn²⁺ ions catalytic pocket, while SIR2 requires NAD⁺dependent action [4]. Class I is present in the nucleus, where HDAC1 and HDAC2 is more restricted due to deprivation of Nucleus Export Signal (NES), but HDAC3 contains both NES and Nucleus Import Signal (NIS). Class II shuttles to and fro the nucleus in response to various cellular signals.

1.2. Mechanism of action:

HDAC activity is to remove the acetyl group, resulting hypoacetylation of histone protein, thus tightening the DNA wrapping around the nucleosomes, thereby decreasing the chances of Transcription factor binding. Charge relay system is the mechanism followed which needs co-factor, Zn²⁺. The HDAC inhibitor replaces the Zn²⁺ ion and inhibits the deacetylation. It consists of the Zinc chelating group, spacer group having hydrophobic properties and enzyme binding group of aromatic structure [46].

1.3. HDACi in cancer:

Over-expressed HDAC induces the uncontrolled cell proliferation by silencing the p21 and p27 gene expression, inhibitor to cyclin dependent kinase (cdk). HDAC inhibitor (HDACi), induces the cell cycle block by inhibiting the proliferation and induction of cdk inhibitor, (p21Waf1) [25]. The p21Waf1 is being regulated under the influence of the Mdm2, mouse double minus 2 encoding oncogenes, through polyubiquitination and proteosomal degradation. The cardiovascular transcription factor such as Kruppel-like factor 5 is being negatively delimited by HDAC1. The retinoblastoma protein, present within a complex and suppresses cell proliferation, entices the HDACs to the chromatic to initiate the deacetylase histones [26]. The classes of HDAC2 inhibitors are under research and clinical trials for its development as the anti-cancer drug, such as the Hydroxamic acid, cyclic tetra peptides etc. [16]. Example:

1. Cyclin depsipeptide, compound present in the Symploca sp is available as Largazole, which shows its potent inhibition in class I HDACs [35].

2. Vorinostat, chemotherapeutic agent in cutaneous T-cell lymphoma (CTCL) [37]

3. Valproic acid, also an antiepileptic drug to cure the depression [45].

1.4. HDAC 2:

It is a part of Class I HDAC family, that are gears of co-rest complex inactivating the neuronal gene expression in non-neuronal gene. It plays an imperative role in preventing the cardiac arrhythmia and dilated cardiomyopathy in mice. 21% of investigated cancer was due to damage of HDAC2 protein expression and microsatellite instability [36] [14].

The up regulation of HDAC 2 is allied with the colorectal cancer, cervical dysplasia, invasive carcinoma and advanced stage disease in gastric and prostate cancer. Table 1.1 shows the know down of HDAC2 in cancer and their consequences.

Table 1.1: Knock out of HDAC2 in cancer and its consequences

Knockdown of HDAC2 in cancer	Consequences
Cervical cancer [12]	Increased p21 expression, Increased apoptosis
Breast Cancer [10]	Increased p53 DNA binding activity, Decreased proliferation and cellular senescence
Chronic lymphocytic leukemia [13]	Increased TRAIL induced apoptosis
Neuroblastoma cell lines [28]	Increased apoptosis
Estrogen/Progesterone Positive Breast Cancer Cell Line [3]	Tamoxifen induced apoptosis

The secondary metabolites are the diverse organic compounds that do not participate directly in the growth and development of the source it has been derived from, such as fungi, plants. Instead, they are proven to be anti-inflammatory, anti-cancer, anti-diabetic agents, hence evolving as a new lead for various incurable disease. They are suggested to be invitro HDAC inhibitor.

The aim of the study is to evaluate the drug likeliness and the determination of the action of secondary metabolites against the active site of the HDAC-2 by Insilco approach. It would be an initiative towards the development of opting natural compound as a lead for the treatment of disease caused due to the HDAC protein.

The initial screening of the compounds is done by “Rule of 5” set by Lipinski et al to evaluate the physio-chemical properties and molecular features of the orally taken drug, that includes five parameters; molecular weight, Log P, H-bond donor, H-bond acceptor and rotatable bond. This will be followed by the molecular docking [24].

2. MATERIALS AND METHODS:

2.1. Bioactive compounds from various sources:

The secondary metabolites which showed HDACi properties towards HDAC class I was taken and the canonical SMILES were retrieved from the PubChem database. The Lipinski Rule of Five were verified by the online software SwissADME. Table 2.1. shows the compounds derived from Pubchem database.

2.2. HDAC 2 Protein Structure:

The 3D protein Structure of the HDAC (PDB-3MAX) was retrieved from the PDB protein database. (Fig-1). A ‘clean input file’ was engendered by removing water molecules, ions, ligands and subunits not involved in ligand binding from the original structure file for the protein-ligand complexes study. The resulting receptor model was saved to a PDB file, companionable with ArgusLab.

2.3. Docking studies using ArgusLab 4.0:

Docking studies were completed using the secondary metabolites in Table-1 against the HDAC-2 protein using ArgusLab4.0, a freely available Windows Platform by Planaria Software. ArgusLab facilitates flexible ligand docking via constructing torsion tree and grids of the ligand that edge the binding.

2.4. Discovery Studio Visualizer 3.1:

A widely available free software that helps in envisaging the macromolecule-ligand interactions, Discovery Studio Visualizer 3.1, developed and distributed by Accelrys, is used to study the simulation of small molecules and large macromolecules. The objective behind the use of this software includes structure-based design, simulations, ligand design, macromolecule engineering, macromolecule design and validation (tools for antibody design and optimization, protein-protein docking), and pharmacophore modeling. Generation of 2D and 3D structures are enabled to visualize and analyze the ligand-protein interaction patterns between them.

Table 2.1: Details of the secondary metabolites retrieved from PubMed database

S. No.	Compound	IUPAC Name	Formula	Chemical Structure
1.	Actinomycin D [21]	2-amino-4,6-dimethyl-3-oxo-1-N,9-N-bis[(3R,6S,7R,10S,16S)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propan-2-yl)-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]phenoxazine-1,9-dicarboxamide	C₆₂H₈₆N₁₂O₁₆
2.	Amamistatin [44]	[(3S)-1-[[(3S)-1-hydroxy-2-oxoazepan-3-yl]amino]-2,2-dimethyl-1-oxodecan-3-yl] (2R)-6-[formyl(hydroxy)amino]-2-[[2-(2-hydroxy-5-methoxyphenyl)-5-methyl-1,3-oxazole-4-carbonyl]amino]hexanoate	C37H55N5O11
3.	Apicidin [18]	(3S,6S,9S,12R)-3-[(2S)-butan-2-yl]-6-[(1-methoxyindol-3-yl)methyl]-9-(6-oxooctyl)-1,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,11-tetrone	C₃₄H₄₉N₅O₆
4.	Apigenin [32]	5,7-dihydroxy-2-(4-hydroxyphenyl) chromen-4-one	C₁₅H₁₀O₅
5.	Butein [30]	(E)-1-(2,4-dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)prop-2-en-1-one	C₁₅H₁₂O₅
6.	Chlamydocin [27]	(3S,9S,12R)-3-benzyl-6,6-dimethyl-9-[6-(oxiran-2-yl)-6-oxohexyl]-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone	C₂₈H₃₈N₄O₆
7.	Chrysin [31]	5,7-dihydroxy-2-phenylchromen-4-one	C₁₅H₁₀O₄
8.	Curcumin [40]	(1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione	C₂₁H₂₀O₆
9.	Cycloheximide [39]	4-[(2R)-2-[(1S,3S,5S)-3,5-dimethyl-2-oxocyclohexyl]-2-hydroxyethyl]piperidine-2,6-dione	C₁₅H₂₃NO₄
10.	Depudecin [20]	(1R)-1-[(2S,3S)-3-[(E)-2-[(2S,3S)-3-[(1R)-1-hydroxyethyl]oxiran-2-yl]ethenyl]oxiran-2-yl]prop-2-en-1-ol	C₁₁H₁₆O₄
11.	Diindolymethane (DIM) [23]	3-(1H-indol-3-ylmethyl)-1H-indole	C₁₇H₁₄N₂
12.	Emodin [8]	1,3,8-trihydroxy-6-methylanthracene-9,10-dione	C₁₅H₁₀O₅
13.	FK 228- romidepsin [38]	(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo [8.7.6]tricos-16-ene-3,6,9,19,22-pentone	C₂₄H₃₆N₄O₆S₂
14.	Genistein [34]	5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one	C₁₅H₁₀O₅
15.	Homobutein [30]	(E)-1-(2,4-dihydroxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one	C₁₆H₁₄O₅
16.	Isoliquiritigenin [30]	(E)-1-(2,4-dihydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one	C₁₅H₁₂O₄
17.	Kaempferol [1]	3,5,7-trihydroxy-2-(4-hydroxyphenyl)chromen-4-one	C₁₅H₁₀O₆
18.	Largazole [7]	S-[(E)-4-[(5R,8S,11S)-5-methyl-6,9,13-trioxo-8-propan-2-yl-10-oxa-3,17-dithia-7,14,19,20-tetrazatricyclo[14.2.1.12,5]icosa-1(18),2(20),16(19)-trien-11-yl]but-3-enyl] octanethioate	C₂₉H₄₂N₄O₅S₃
19.	Leptomycin [47]	(2E,5S,6R,7S,9R,10E,12E,15R,16E,18E)-17-ethyl-6-hydroxy-3,5,7,9,11,15-hexamethyl-19-[(2S,3S)-3-methyl-6-oxo-2,3-dihydropyran-2-yl]-8-oxononadeca-2,10,12,16,18-pentaenoic acid	C₃₃H₄₈O₆
20.	Oroxylin A [6]	5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one	C₁₆H₁₂O₅
21.	Oxamflatin [19]	(E)-5-[3-(benzenesulfonamido)phenyl]-N-hydroxypent-2-en-4-ynamide	C₁₇H₁₄N₂O₄S
22.	Pomiferin [41]	3-(3,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl-6-(3-methylbut-2-enyl)pyrano[2,3-h]chromen-4-one	C₂₅H₂₄O₆
23.	Sphingosine 1-phosphate [9]	[(E,2S,3R)-2-amino-3-hydroxyoctadec-4-enyl] dihydrogen phosphate	C₁₈H₃₈NO₅P
24.	Spiruchostatin [5]	(1S,5S,6R,9S,15Z,20R)-5-hydroxy-20-methyl-6-propan-2-yl-2-oxa-11,12-dithia-7,19,22-triazabicyclo[7.7.6]docos-15-ene-3,8,18,21-tetrone	C₂₀H₃₁N₃O₆S₂
25.	Tectochrysin [42]	5-hydroxy-7-methoxy-2-phenylchromen-4-one	C₁₆H₁₂O₄
26.	Thujaplicin [29]	2-hydroxy-3-propan-2-ylcyclohepta-2,4,6-trien-1-one	C₁₀H₁₂O₂
27.	Trapoxin B [15]	(3S,6S,9S,12R)-3,6-dibenzyl-9-[6-[(2S)-oxiran-2-yl]-6-oxohexyl]-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone	C₃₃H₄₀N₄O₆
28.	Trichostatin A [47]	(2E,4E,6R)-7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxohepta-2,4-dienamide	C₁₇H₂₂N₂O₃

Figure 3.1: Histone Deactylase 2 (HDAC2) Protein with PDB ID: 3MAX with chains A, B and C in complex with a selective inhibitor and ligand interaction diagram

Table 3.1: Lipinski rule Properties of the secondary metabolites.

Compound	Molecular Weight	#H-bond acceptors	#H-bond donors	MR	iLOGP
Apigenin	270.24	5	3	73.99	1.89
Butein	272.25	5	4	74.34	1.66
Chrysin	254.24	4	2	71.97	2.27
Curcumin	368.38	6	2	102.8	3.27
Cycloheximide	281.35	4	2	78.47	2.16
Depudecin	212.24	4	2	54.31	2.37
Diindolymethane (DIM)	246.31	0	2	79.61	1.99
Emodin	270.24	5	3	70.78	1.81
Entinostat	376.41	4	3	106.4	2.04
Genistein	270.24	5	3	73.99	1.91
Homobutein	286.28	5	3	78.81	2.35
isoliquiritigenin	256.25	4	3	72.32	2.02
Kaempferol	286.24	6	4	76.01	1.7
Oroxylin A	284.26	5	2	78.46	2.61
Oxamflatin	342.37	4	3	89.17	1.09
Pomiferin	420.45	6	3	121.83	3.87
Sphingosine 1-phosphate	379.47	6	4	104.11	3.41
Tectochrysin	268.26	4	1	76.44	2.88
Thujaplicin	164.2	2	1	49.32	2.11
Trichostatin A	302.37	3	2	87.28	2.5

Figure 3.6: 3D and 2D ligand interaction diagram of the compound Butein against the active site of HDAC 2 protein (PDB ID: 3MAX)

Table 3.2: Docking Score and Interaction of the Secondary Metabolites from various sources Histone Deacetylase 2 (HDAC2) enzyme

Compound	Interaction energy	No. of Vander Waal's Interactions	Pi-Alkyl Interaction and H-bond interaction	Total Bonds
Apigenin	-8.1605	ALA 141, ILE 40, ILE 24, PRO 37, MET 35, LEU 144, TYR 29, PHE 155		8
Butein	-10.0837	ALA 141, ASN 139, ASP 21, ILE 24, ILE 40, TYR 19	TYR 18, TRP 140, VAL 138	9
Chrysin	-10.558	CYS 156, LEU 144, MET 35, PHE 108, PHE 155	CYS 115, LEU 111, PHE 114, TYR 157	9
Curcumin	-6.07203	CYS 156, HIS 183, LEU 144, MET 35, TYR 308	TYR 29	6
Cycloheximide	-9.06187	LEU 166, LEU 169, THR 195	TYR 72	4
Depudecin	-7.1385	ASN 139, TRP 140	ALA 141, ILE 24, ILE 40, TYR 20, ASP 21	7
Diindolymethane (DIM)	-11.075	ILE 24, ILE 40	MET 35, PRO 37, TYR 29, ALA 141	6
Emodin	-7.60032	ALA 141, ILE 24, ILE 40, PHE 114, MET 35, TYR 29		6
Genistein	-8.23822	ASP 21, ILE 24, ILE 40, TRP 140, TYR 18, TYR 19, TYR 20	ALA 141	8
Homobutein	-8.6614	ALA 141, ASN 139, ILE 40, HIS 44, THR 43, TRP 140, TYR 19, TYR 20		8
Isoliquiritigenin	-10.6969	ALA 141, ILE 24, ILE 40, LYS 36, MET 35, PHE 114, PHE 155, PRO 37	ARG 39	9
Kaempferol	-7.43818	CYS 156, GLY 154, LEU 144, MET 35, PHE 155, PRO 37		6
Oroxylin A	-5.7968	LEU 144, MET 35, PHE 155	ARG 39	4
Oxamflatin	-11.7569	ALA 141, CYS 156, ILE 24, ILE 40, GLY 154, LEU 144, MET 35, PHE 155, PRO 37, TYR 29	PHE 114, TYR 308	12
Pomiferin	-9.85159	ALA 141, CYS 156, GLY 154, LEU 144, MET 35, PHE 155, SER 118, TYR 29	ILE 24, ILE 40, PHE 114, PRO 37	12
Sphingosine 1-phosphate	-13.209	ARG 39, GLY 143, GLY 154, HIS 145, HIS 146, HIS 183, MET35, PHE 155	ILE 40, PHE 114, PRO 37, CYS 156, TYR 308	13
Tectochrysin	-8.8705	PHE 155, TYR 29	ILE 24, ILE 40, LEU 144, MET 35, PHE 114, PRO 37	8
Thujaplicin	-9.53688	CYS 115, ILE 84, LEU 81, LEU 111, PHE 112, TYR 157		6
Trichostatin A	-5.0614	ARG 39, CYS 156, PHE 155, TYR 157, VAL 158	ALA 141, CYS 115	7

4. CONCLUSION:

The progress of natural compounds with biological activity is required for the treatment of diseases like neurodegenerative or cardiovascular diseases by inhibiting the over expressive activity of the HDAC. In the present study, docking results discovered the binding of secondary metabolites with the Histone Deacetylase 2. Among those compounds, “Sphingosine 1-phosphate” and “oxamflatin” have binding energies greater than −11.88 kCal/mol at the active site region of HDAC2 and gratify Lipinski’s rule, the basis for the lead to be used as an oral drug. Hence, it can be concluded that the secondary metabolites could be potent drugs for HDAC inhibitor and this could be more used for research as a pharmacophore for the development of HDAC enzyme inhibitors.

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Received on 17.02.2020 Modified on 08.05.2020

Research J. Pharm. and Tech. 2021; 14(2):673-684.

DOI: 10.5958/0974-360X.2021.00120.7