Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach

Abstract Histone deacetylases (HDAC) contain eighteen isoforms that can be divided into four classes. Of these isoform enzymes, class IIa (containing HDAC4, 5, 7 and 9) target unique substrates, some of which are client proteins associated with epigenetic control. Class IIa HDACs are reportedly asso...

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Autores principales:	Kai-Cheng Hsu, Chang-Yi Liu, Tony Eight Lin, Jui-Hua Hsieh, Tzu-Ying Sung, Hui-Ju Tseng, Jinn-Moon Yang, Wei-Jan Huang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7b99dbc22d7541d3950827cebd4867ae
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spelling	oai:doaj.org-article:7b99dbc22d7541d3950827cebd4867ae2021-12-02T16:06:37ZNovel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach10.1038/s41598-017-03417-12045-2322https://doaj.org/article/7b99dbc22d7541d3950827cebd4867ae2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03417-1https://doaj.org/toc/2045-2322Abstract Histone deacetylases (HDAC) contain eighteen isoforms that can be divided into four classes. Of these isoform enzymes, class IIa (containing HDAC4, 5, 7 and 9) target unique substrates, some of which are client proteins associated with epigenetic control. Class IIa HDACs are reportedly associated with some neuronal disorders, making HDACs therapeutic targets for treating neurodegenerative diseases. Additionally, some reported HDAC inhibitors contain hydroxamate moiety that chelates with zinc ion to become the cofactor of HDAC enzymes. However, the hydroxamate functional group is shown to cause undesirable effects and has poor pharmacokinetic profile. This study used in silico virtual screening methodology to identify several nonhydroxamate compounds, obtained from National Cancer Institute database, which potentially inhibited HDAC4. Comparisons of the enzyme inhibitory activity against a panel of HDAC isoforms revealed these compounds had strong inhibitory activity against class IIa HDACs, but weak inhibitory activity against class I HDACs. Further analysis revealed that a single residue affects the cavity size between class I and class IIa HDACs, thus contributing to the selectivity of HDAC inhibitors discovered in this study. The discovery of these inhibitors presents the possibility of developing new therapeutic treatments that can circumvent the problems seen in traditional hydroxamate-based drugs.Kai-Cheng HsuChang-Yi LiuTony Eight LinJui-Hua HsiehTzu-Ying SungHui-Ju TsengJinn-Moon YangWei-Jan HuangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kai-Cheng Hsu Chang-Yi Liu Tony Eight Lin Jui-Hua Hsieh Tzu-Ying Sung Hui-Ju Tseng Jinn-Moon Yang Wei-Jan Huang Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach
description	Abstract Histone deacetylases (HDAC) contain eighteen isoforms that can be divided into four classes. Of these isoform enzymes, class IIa (containing HDAC4, 5, 7 and 9) target unique substrates, some of which are client proteins associated with epigenetic control. Class IIa HDACs are reportedly associated with some neuronal disorders, making HDACs therapeutic targets for treating neurodegenerative diseases. Additionally, some reported HDAC inhibitors contain hydroxamate moiety that chelates with zinc ion to become the cofactor of HDAC enzymes. However, the hydroxamate functional group is shown to cause undesirable effects and has poor pharmacokinetic profile. This study used in silico virtual screening methodology to identify several nonhydroxamate compounds, obtained from National Cancer Institute database, which potentially inhibited HDAC4. Comparisons of the enzyme inhibitory activity against a panel of HDAC isoforms revealed these compounds had strong inhibitory activity against class IIa HDACs, but weak inhibitory activity against class I HDACs. Further analysis revealed that a single residue affects the cavity size between class I and class IIa HDACs, thus contributing to the selectivity of HDAC inhibitors discovered in this study. The discovery of these inhibitors presents the possibility of developing new therapeutic treatments that can circumvent the problems seen in traditional hydroxamate-based drugs.
format	article
author	Kai-Cheng Hsu Chang-Yi Liu Tony Eight Lin Jui-Hua Hsieh Tzu-Ying Sung Hui-Ju Tseng Jinn-Moon Yang Wei-Jan Huang
author_facet	Kai-Cheng Hsu Chang-Yi Liu Tony Eight Lin Jui-Hua Hsieh Tzu-Ying Sung Hui-Ju Tseng Jinn-Moon Yang Wei-Jan Huang
author_sort	Kai-Cheng Hsu
title	Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach
title_short	Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach
title_full	Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach
title_fullStr	Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach
title_full_unstemmed	Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach
title_sort	novel class iia-selective histone deacetylase inhibitors discovered using an in silico virtual screening approach
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/7b99dbc22d7541d3950827cebd4867ae
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Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach

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