Computational design of a time-dependent histone deacetylase 2 selective inhibitor

Jingwei Zhou, Min Li, Nanhao Chen, Shenglong Wang, Hai Bin Luo, Yingkai Zhang, Ruibo Wu

Research output: Contribution to journalArticle

Abstract

Development of isoform-selective histone deacetylase (HDAC) inhibitors is of great biological and medical interest. Among 11 zinc-dependent HDAC isoforms, it is particularly challenging to achieve isoform inhibition selectivity between HDAC1 and HDAC2 due to their very high structural similarities. In this work, by developing and applying a novel de novo reaction-mechanism-based inhibitor design strategy to exploit the reactivity difference, we have discovered the first HDAC2-selective inhibitor, β-hydroxymethyl chalcone. Our bioassay experiments show that this new compound has a unique time-dependent selective inhibition on HDAC2, leading to about 20-fold isoform-selectivity against HDAC1. Furthermore, our ab initio QM/MM molecular dynamics simulations, a state-of-the-art approach to study reactions in biological systems, have elucidated how the β-hydroxymethyl chalcone can achieve the distinct time-dependent inhibition toward HDAC2.

Original languageEnglish (US)
Pages (from-to)687-692
Number of pages6
JournalACS Chemical Biology
Volume10
Issue number3
DOIs
StatePublished - Mar 20 2015

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Histone Deacetylase 2
Protein Isoforms
Chalcone
Histone Deacetylase Inhibitors
Histone Deacetylases
Bioassay
Biological systems
Molecular Dynamics Simulation
Biological Assay
Molecular dynamics
Zinc
Computer simulation
Experiments

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Computational design of a time-dependent histone deacetylase 2 selective inhibitor. / Zhou, Jingwei; Li, Min; Chen, Nanhao; Wang, Shenglong; Luo, Hai Bin; Zhang, Yingkai; Wu, Ruibo.

In: ACS Chemical Biology, Vol. 10, No. 3, 20.03.2015, p. 687-692.

Research output: Contribution to journalArticle

Zhou, Jingwei ; Li, Min ; Chen, Nanhao ; Wang, Shenglong ; Luo, Hai Bin ; Zhang, Yingkai ; Wu, Ruibo. / Computational design of a time-dependent histone deacetylase 2 selective inhibitor. In: ACS Chemical Biology. 2015 ; Vol. 10, No. 3. pp. 687-692.
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