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

Kai Cheng Hsu, Chang Yi Liu, Tony Eight Lin, Jui Hua Hsieh, Tzu Ying Sung, Hui Ju Tseng, Jinn Moon Yang, Wei Jan Huang

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Article number3228
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - Dec 1 2017

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Histone Deacetylase Inhibitors
Histone Deacetylases
Computer Simulation
Protein Isoforms
Enzymes
National Cancer Institute (U.S.)
Epigenomics
Neurodegenerative Diseases
Zinc
Pharmacokinetics
Databases
Ions
Therapeutics
Pharmaceutical Preparations
Proteins

ASJC Scopus subject areas

  • General

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Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach. / Hsu, Kai Cheng; Liu, Chang Yi; Lin, Tony Eight; Hsieh, Jui Hua; Sung, Tzu Ying; Tseng, Hui Ju; Yang, Jinn Moon; Huang, Wei Jan.

In: Scientific Reports, Vol. 7, No. 1, 3228, 01.12.2017.

Research output: Contribution to journalArticle

Hsu, Kai Cheng ; Liu, Chang Yi ; Lin, Tony Eight ; Hsieh, Jui Hua ; Sung, Tzu Ying ; Tseng, Hui Ju ; Yang, Jinn Moon ; Huang, Wei Jan. / Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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