Zhou Jingwei, Li Min, Chen Nanhao, Wang Shenglong, Luo Hai-Bin, Zhang Yingkai, Wu Ruibo
†School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P.R. China.
‡Department of Chemistry, New York University, New York, New York 10003, United States.
ACS Chem Biol. 2015 Mar 20;10(3):687-92. doi: 10.1021/cb500767c. Epub 2015 Jan 2.
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.
开发亚型选择性组蛋白去乙酰化酶（HDAC）抑制剂具有重大的生物学和医学意义。在11种锌依赖性HDAC亚型中，由于HDAC1和HDAC2的结构非常相似，要实现它们之间的亚型抑制选择性极具挑战性。在这项工作中，通过开发并应用一种基于从头反应机制的新型抑制剂设计策略来利用反应性差异，我们发现了首个HDAC2选择性抑制剂β-羟甲基查耳酮。我们的生物测定实验表明，这种新化合物对HDAC2具有独特的时间依赖性选择性抑制作用，对HDAC1的亚型选择性约为20倍。此外，我们的从头算QM/MM分子动力学模拟是研究生物系统中反应的一种先进方法，它阐明了β-羟甲基查耳酮如何对HDAC2实现独特的时间依赖性抑制。
