Structure-activity studies on splitomicin derivatives as sirtuin inhibitors and computational prediction of binding mode
Structure-activity studies on splitomicin derivatives as sirtuin inhibitors and computational prediction of binding mode
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DOI：
10.1021/jm700972e
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发表时间：
2008-03-13
影响因子：
7.3
通讯作者：
Jung, Manfred
中科院分区：
文献类型：
--
作者：
Neugebauer, Robert C.;Uchiechowska, Urszula;Jung, Manfred
依赖NAD（+）的组蛋白去乙酰化酶（sirtuins）是在组蛋白和其他蛋白质中从赖氨酸中切割乙酰基的酶。有效的选择性sirtuin抑制剂是研究这些酶的生物学功能的有趣工具，可能是未来治疗癌症的药物。Splitomicin是最早发现的两种用于酵母sirtuins的抑制剂之一，但对人类酶的抑制作用相当弱。我们详细介绍了splitomicin衍生物的构效关系及其对重组Sirt2的抑制作用。为了使实验结果合理化，我们进行了配体对接，然后进行了分子力学泊松-玻尔兹曼/表面积（MM-PBSA）计算。这些分析提示了β -苯基分裂菌素与人类Sirt2相互作用的分子基础。基于蛋白质的虚拟筛选导致鉴定出一种新的Sirt2抑制剂化学型。所选择的抑制剂在MCF7乳腺癌细胞中显示出抗增殖和微管蛋白超乙酰化的特性，并且有希望进一步优化作为潜在的抗癌药物。
NAD(+)-dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysines in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of those enzymes and may be future drugs for the treatment of cancer. Splitomicin was among the first two inhibitors that were discovered for yeast sirtuins but showed rather weak inhibition on human enzymes. We present detailed structure-activity relationships on splitomicin derivatives and their inhibition of recombinant Sirt2. To rationalize our experimental results, ligand docking followed by molecular mechanics Poisson - Boltzmann/surface area (MM-PBSA) calculations were carried out. These analyses suggested a molecular basis for the interaction of the beta-phenylsplitomicins with human Sirt2. Protein-based virtual screening resulted in the identification of a novel Sirt2 inhibitor chemotype. Selected inhibitors showed antiproliferative properties and tubulin hyperacetylation in MCF7 breast cancer cells and are promising candidates for further optimization as potential anticancer drugs.