Melesina Jelena, Simoben Conrad V, Praetorius Lucas, Bülbül Emre F, Robaa Dina, Sippl Wolfgang
Institute of Pharmacy, Martin Luther University of Halle - Wittenberg, Kurt Mothes Straße 3, 06120, Halle (Saale), Germany.
ChemMedChem. 2021 May 6;16(9):1336-1359. doi: 10.1002/cmdc.202000934. Epub 2021 Feb 19.
This review classifies drug-design strategies successfully implemented in the development of histone deacetylase (HDAC) inhibitors, which have many applications including cancer treatment. Our focus is on especially demanded selective HDAC inhibitors and their structure-activity relationships in relation to corresponding protein structures. The main part of the paper is divided into six subsections each narrating how optimization of one of six structural features can influence inhibitor selectivity. It starts with the impact of the zinc binding group on selectivity, continues with the optimization of the linker placed in the substrate binding tunnel as well as the adjustment of the cap group interacting with the surface of the protein, and ends with the addition of groups targeting class-specific sub-pockets: the side-pocket-, lower-pocket- and foot-pocket-targeting groups. The review is rounded off with a conclusion and an outlook on the future of HDAC inhibitor design.
本综述对在组蛋白去乙酰化酶（HDAC）抑制剂开发中成功实施的药物设计策略进行了分类，这些抑制剂有包括癌症治疗在内的诸多应用。我们重点关注特别需要的选择性HDAC抑制剂及其与相应蛋白质结构相关的构效关系。论文主体分为六个小节，每节讲述六种结构特征之一的优化如何影响抑制剂的选择性。它从锌结合基团对选择性的影响开始，接着是对位于底物结合通道中的连接子的优化以及与蛋白质表面相互作用的帽基团的调整，最后是添加靶向特定类别亚口袋的基团：侧口袋靶向基团、下口袋靶向基团和足口袋靶向基团。综述以结论和对HDAC抑制剂设计未来的展望收尾。
