Hou Xuben, Du Jintong, Liu Renshuai, Zhou Yi, Li Minyong, Xu Wenfang, Fang Hao
†Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong 250012, China.
‡Shandong Cancer Hospital and Institute, Jinan, Shandong 250117, China.
J Chem Inf Model. 2015 Apr 27;55(4):861-71. doi: 10.1021/ci500762z. Epub 2015 Mar 16.
As key regulators of epigenetic regulation, human histone deacetylases (HDACs) have been identified as drug targets for the treatment of several cancers. The proper recognition of zinc-binding groups (ZBGs) will help improve the accuracy of virtual screening for novel HDAC inhibitors. Here, we developed a high-specificity ZBG-based pharmacophore model for HDAC8 inhibitors by incorporating customized ZBG features. Subsequently, pharmacophore-based virtual screening led to the discovery of three novel HDAC8 inhibitors with low micromole IC50 values (1.8-1.9 μM). Further studies demonstrated that compound H8-A5 was selective for HDAC8 over HDAC 1/4 and showed antiproliferation activity in MDA-MB-231 cancer cells. Molecular docking and molecular dynamic studies suggested a possible binding mode for H8-A5, which provides a good starting point for the development of HDAC8 inhibitors in cancer treatment.
作为表观遗传调控的关键调节因子，人类组蛋白去乙酰化酶（HDACs）已被确定为治疗多种癌症的药物靶点。正确识别锌结合基团（ZBGs）将有助于提高新型HDAC抑制剂虚拟筛选的准确性。在此，我们通过纳入定制的ZBG特征，开发了一种基于ZBG的高特异性HDAC8抑制剂药效团模型。随后，基于药效团的虚拟筛选发现了三种新型HDAC8抑制剂，其IC50值低至微摩尔级别（1.8 - 1.9 μM）。进一步研究表明，化合物H8 - A5对HDAC8的选择性高于HDAC 1/4，并在MDA - MB - 231癌细胞中显示出抗增殖活性。分子对接和分子动力学研究提出了H8 - A5可能的结合模式，这为开发用于癌症治疗的HDAC8抑制剂提供了一个良好的起点。
