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

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, ?-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 ?-hydroxymethyl chalcone can achieve the distinct time-dependent inhibition toward HDAC2.

SUBMITTER: Zhou J

PROVIDER: S-EPMC4372102 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Zhou Jingwei J Li Min M Chen Nanhao N Wang Shenglong S Luo Hai-Bin HB Zhang Yingkai Y Wu Ruibo R

ACS chemical biology 20150102 3

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 ...[more]

PMID: 25546141

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