A Computational Approach to Investigate the HDAC6 and HDAC10 Binding Propensity of Psidium guajava-derived Compounds as Potential Anticancer Agents

2020 ◽  
Vol 20 ◽  
Author(s):  
Kayode Ezekiel Adewole ◽  
Ahmed Adebayo Ishola
Keyword(s):  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Histone Deacetylases ◽  
Active Sites ◽  
Epigenetic Modification ◽  
Psidium Guajava ◽  
Asiatic Acid ◽  
Histone Deacetylase 6 ◽  
Lipinski’S Rule ◽  
Discovery Studio

Background: Psidium guajava is consumed as food and used for medicinal purposes around the world; with studies reporting its antiproliferative effects via different biochemical mechanisms, yet its modulatory effects on epigenetic modification of DNA molecules via histone deacetylases (HDACs) is largely unknown. Objective: This study was carried out to investigate the binding propensity of Psidium guajava-derived compounds on the activities of histone deacetylase 6 (HDAC6) and histone deacetylase 10 (HDAC10) for possible application as anticancer agents using in silico methods. Methods: 59 guava-derived compounds and apicidin, a standard HDAC inhibitor, were docked with HDAC6 and HDAC10 using AutodockVina after modeling (SWISS-MODEL server) and validating (ERRAT (27) and VERIFY-3D) the structure of HDAC10, while their molecular interactions with the HDACs were viewed with Discovery Studio Visualizer. Prediction of binding sites, surface structural pockets, active sites, area, shape and volume of every pocket and internal cavities of proteins were done using Computed Atlas of Surface Topography of proteins (CASTp) server, while Absorption, Distribution Metabolism and Excretion (ADME) study of notable compounds was done using Swiss online ADME web tool. Results: 2α-hydroxyursolic acid, asiatic acid, betulinic acid, crategolic acid, guajadial A and B, guavacoumaric acid, guavanoic acid, ilelatifol D, isoneriucoumaric acid, jacoumaric acid, oleanolic acid, psiguadial A, B and C demonstrated maximum interaction with the selected HDACs. ADME studies reveal that although isoneriucoumaric and jacoumaric acid ranked very high as HDAC inhibitors, they both violated the Lipinski’s rule of 5. Conclusion: This study identified 13 drugable guava-derived compounds that can be enlisted for further studies as potential HDAC6 and HDAC10 inhibitors.

A Homogeneous Nonisotopic Histone Deacetylase Activity Assay

2003 ◽  
Vol 8 (1) ◽  
pp. 89-95 ◽  
Author(s):  
Birgit Heltweg ◽  
Manfred Jung
Keyword(s):  
Drug Discovery ◽  
Fluorescence Quenching ◽  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Histone Deacetylases ◽  
Activity Assay ◽  
Animal Testing ◽  
Hdac Activity

Histone deacetylases (HDACs) are important regulators of transcription, and their inhibitors are a promising class of anticancer agents. The methods for the determination of HDAC activity and its inhibition that are currently available suffer from various drawbacks, such as animal testing, radioactive substrates, or limited throughput. Therefore, a fast nonisotopic method for the measurement of HDAC activity is highly desirable. The authors present such an assay that relies on the fluorescent HDAC substrate developed previously in their group. After incubation of the substrate with the enzyme, a derivatization leads to efficient fluorescence quenching in the deacetylated metabolite. Thus, only the fluorescence emitted by the remaining substrate is detected, which allows for a convenient detection of HDAC activity in a homogeneous format that can be performed on multiwell plate readers. This procedure, called HDASH (histone deacetylase assay—homogeneous), should be a valuable tool in transcriptional research and especially drug discovery. ( Journal of Biomolecular Screening 2003:89-95)

scholarly journals Cystathionine γ-lyase protects vascular endothelium: a role for inhibition of histone deacetylase 6

2017 ◽  
Vol 312 (4) ◽  
pp. H711-H720 ◽  
Author(s):  
Thorsten M. Leucker ◽  
Yohei Nomura ◽  
Jae Hyung Kim ◽  
Anil Bhatta ◽  
Victor Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Histone Deacetylase ◽  
Vascular Endothelium ◽  
High Fat Diet ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Oxidized Ldl ◽  
Hdac Inhibitors ◽  
Histone Deacetylase 6 ◽  
High Fat

Endothelial cystathionine γ-lyase (CSEγ) contributes to cardiovascular homeostasis, mainly through production of H2S. However, the molecular mechanisms that control CSEγ gene expression in the endothelium during cardiovascular diseases are unclear. The aim of the current study is to determine the role of specific histone deacetylases (HDACs) in the regulation of endothelial CSEγ. Reduced CSEγ mRNA expression and protein abundance were observed in human aortic endothelial cells (HAEC) exposed to oxidized LDL (OxLDL) and in aortas from atherogenic apolipoprotein E knockout (ApoE−/−) mice fed a high-fat diet compared with controls. Intact murine aortic rings exposed to OxLDL (50 μg/ml) for 24 h exhibited impaired endothelium-dependent vasorelaxation that was blocked by CSEγ overexpression or the H2S donor NaHS. CSEγ expression was upregulated by pan-HDAC inhibitors and by class II-specific HDAC inhibitors, but not by other class-specific inhibitors. The HDAC6 selective inhibitor tubacin and HDAC6-specific siRNA increased CSEγ expression and blocked OxLDL-mediated reductions in endothelial CSEγ expression and CSEγ promoter activity, indicating that HDAC6 is a specific regulator of CSEγ expression. Consistent with this finding, HDAC6 mRNA, protein expression, and activity were upregulated in OxLDL-exposed HAEC, but not in human aortic smooth muscle cells. HDAC6 protein levels in aortas from high-fat diet-fed ApoE−/− mice were comparable to those in controls, whereas HDAC6 activity was robustly upregulated. Together, our findings indicate that HDAC6 is upregulated by atherogenic stimuli via posttranslational modifications and is a critical regulator of CSEγ expression in vascular endothelium. Inhibition of HDAC6 activity may improve endothelial function and prevent or reverse the development of atherosclerosis. NEW & NOTEWORTHY Oxidative injury to endothelial cells by oxidized LDL reduced cystathionine γ-lyase (CSEγ) expression and H2S production, leading to endothelial dysfunction, which was prevented by histone deacetylase 6 (HDAC6) inhibition. Our data suggest HDAC6 as a novel therapeutic target to prevent the development of atherosclerosis.

scholarly journals Ligand Based Pharmacophore Modeling and Virtual Screening Studies to Design Novel HDAC2 Inhibitors

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Naresh Kandakatla ◽  
Geetha Ramakrishnan
Keyword(s):  
Virtual Screening ◽  
Histone Deacetylases ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Pharmacophore Modeling ◽  
Hydrogen Bond Acceptor ◽  
Lipinski’S Rule ◽  
Discovery Studio ◽  
Pharmacophore Generation ◽  
Important Therapeutic Target

Histone deacetylases 2 (HDAC2), Class I histone deacetylase (HDAC) family, emerged as an important therapeutic target for the treatment of various cancers. A total of 48 inhibitors of two different chemotypes were used to generate pharmacophore model using 3D QSAR pharmacophore generation (HypoGen algorithm) module in Discovery Studio. The best HypoGen model consists of four pharmacophore features namely, one hydrogen bond acceptor (HBA), and one hydrogen donor (HBD), one hydrophobic (HYP) and one aromatic centres, (RA). This model was validated against 20 test set compounds and this model was utilized as a 3D query for virtual screening to validate against NCI and Maybridge database and the hits further screened by Lipinski’s rule of 5, and a total of 382 hit compounds from NCI and 243 hit compounds from Maybridge were found and were subjected to molecular docking in the active site of HDAC2 (PDB: 3MAX). Finally eight hit compounds, NSC108392, NSC127064, NSC110782, and NSC748337 from NCI database and MFCD01935795, MFCD00830779, MFCD00661790, and MFCD00124221 from Maybridge database, were considered as novel potential HDAC2 inhibitors.

scholarly journals Histone Deacetylase Inhibitors As Potential Therapeutic Agents For Various Disorders

2019 ◽  
Vol 5 (2) ◽  
pp. 235-253
Author(s):  
Kajal Thapa ◽  
Savir Kumar ◽  
Anurag Sharma ◽  
Sandeep Arora ◽  
Amarjot Kaur Grewal ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Epigenetic Modification ◽  
Histone Acetyltransferases ◽  
Lysine Acetylation ◽  
Histone Deacetylases Inhibitors ◽  
Nucleosomal Array ◽  
Key Factor

Epigenetic modification acetylation or deacetylation of histone considered as an important element in various disorders. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are the enzymes which catalyse the acetylation and deacetylation of histone respectively. It helps in regulating the condensation of chromatin and transcription of genes. Lysine acetylation and deacetylation present on the nucleosomal array of histone is the key factor for gene expression and regulation in a normal working living cell. Modification in histone protein will lead to the development of cancer and can cause various neurodegenerative disorders. To safeguard the cells or histone proteins from these diseases histone deacetylase inhibitors are used. In this review, the main focus is upon the role of histone deacetylases inhibitors in various diseases.

PTML Modeling for Alzheimer’s Disease: Design and Prediction of Virtual Multi-Target Inhibitors of GSK3B, HDAC1, and HDAC6

2020 ◽  
Vol 20 (19) ◽  
pp. 1661-1676 ◽  
Author(s):  
Valeria V. Kleandrova ◽  
Alejandro Speck-Planche
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Histone Deacetylase ◽  
Computational Models ◽  
Glycogen Synthase ◽  
Histone Deacetylase 6 ◽  
Ann Model ◽  
Lipinski’S Rule ◽  
Histone Deacetylase 1 ◽  
Model Combining

Background: Alzheimer’s disease is characterized by a progressive pattern of cognitive and functional impairment, which ultimately leads to death. Computational approaches have played an important role in the context of drug discovery for anti-Alzheimer's therapies. However, most of the computational models reported to date have been focused on only one protein associated with Alzheimer's, while relying on small datasets of structurally related molecules. Objective: We introduce the first model combining perturbation theory and machine learning based on artificial neural networks (PTML-ANN) for simultaneous prediction and design of inhibitors of three Alzheimer’s disease-related proteins, namely glycogen synthase kinase 3 beta (GSK3B), histone deacetylase 1 (HDAC1), and histone deacetylase 6 (HDAC6). Methods: The PTML-ANN model was obtained from a dataset retrieved from ChEMBL, and it relied on a classification approach to predict chemicals as active or inactive. Results: The PTML-ANN model displayed sensitivity and specificity higher than 85% in both training and test sets. The physicochemical and structural interpretation of the molecular descriptors in the model permitted the direct extraction of fragments suggested to favorably contribute to enhancing the multitarget inhibitory activity. Based on this information, we assembled ten molecules from several fragments with positive contributions. Seven of these molecules were predicted as triple target inhibitors while the remaining three were predicted as dual-target inhibitors. The estimated physicochemical properties of the designed molecules complied with Lipinski’s rule of five and its variants. Conclusion: This work opens new horizons toward the design of multi-target inhibitors for anti- Alzheimer's therapies.

Histone deacetylase 6– HDAC6– a new regulator of glucocorticoid receptor-mediated metabolic processes

2010 ◽  
Vol 5 (S 01) ◽  
Author(s):  
R Winkler ◽  
M Clemenz ◽  
M Bloch ◽  
A Foryst-Ludwig ◽  
C Böhm ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Histone Deacetylase ◽  
Histone Deacetylase 6 ◽  
Metabolic Processes
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