Rudolf Virchow Center for Experimental Biomedicine, Institute of Structural Biology, University of Würzburg, Josef-Schneider-Straße 2, 97080, Würzburg, Germany.
Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074, Würzburg, Germany.
ChemMedChem. 2018 Oct 8;13(19):2014-2023. doi: 10.1002/cmdc.201800364. Epub 2018 Sep 6.
Based on the similarity between the active sites of the deubiquitylating and deneddylating enzyme ChlaDub1 (Cdu1) and the evolutionarily related protease adenain, a target-hopping screening approach on a focused set of adenain inhibitors was investigated. The cyanopyrimidine-based inhibitors identified represent the first active-site-directed small-molecule inhibitors of Cdu1. High-resolution crystal structures of Cdu1 in complex with two covalently bound cyanopyrimidines, as well as with its substrate ubiquitin, were obtained. These structural data were complemented by enzymatic assays and covalent docking studies to provide insight into the substrate recognition of Cdu1, active-site pocket flexibility and potential hotspots for ligand interaction. Combined, these data provide a strong basis for future structure-guided medicinal chemistry optimization of this cyanopyrimidine scaffold into more potent and selective Cdu1 inhibitors.
基于去泛素化和去端粒酶的 ChlaDub1（Cdu1）的活性位点与进化相关的蛋白酶 adenain 之间的相似性，研究了一种针对一组重点 adenain 抑制剂的靶标跳跃筛选方法。所鉴定的基于氰基嘧啶的抑制剂代表了 Cdu1 的第一个活性位点定向小分子抑制剂。获得了 Cdu1 与两个共价结合的氰基嘧啶以及其底物泛素的高分辨率晶体结构。这些结构数据通过酶测定和共价对接研究进行了补充，以深入了解 Cdu1 的底物识别、活性位点口袋的灵活性以及配体相互作用的潜在热点。综合这些数据为未来基于结构的药物化学优化提供了强有力的基础，将这种氰基嘧啶支架优化为更有效和选择性的 Cdu1 抑制剂。
