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 journalArticlepeer-review


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
Issue number3
StatePublished - Mar 20 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine


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