Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK.
Bioorg Med Chem. 2018 Jul 15;26(11):2992-2995. doi: 10.1016/j.bmc.2018.03.034. Epub 2018 Mar 23.
Thioamide substitution influences hydrogen bond and n → π interactions involved in the conformational stability of protein secondary structures and oligopeptides. Hydroxyproline is the key recognition element of small molecules targeting the von Hippel-Lindau (VHL) E3 ligase, which are of interest as probes of hypoxia signaling and ligands for PROTAC conjugation. We hypothesized that VHL ligands could be a privileged model system to evaluate the contribution of these interactions to protein:ligand complex formation. Herein we report the synthesis of VHL ligands bearing thioamide substitutions at the central hydroxyproline moiety, and characterize their binding by fluorescence polarization, isothermal titration calorimetry, X-ray crystallography and molecular modeling. In spite of a conserved binding mode, the substitution pattern had a pronounced impact on the ligand affinities. Together the results underscore the role of hydrogen bond and n → π interactions in fine tuning hydroxyproline recognition by VHL.
硫代酰胺取代会影响氢键和 n→π 相互作用，这些相互作用涉及蛋白质二级结构和寡肽的构象稳定性。羟脯氨酸是靶向 von Hippel-Lindau (VHL) E3 连接酶的小分子的关键识别元件，这些小分子作为缺氧信号的探针和 PROTAC 缀合的配体很有研究价值。我们假设 VHL 配体可以作为一个特权模型系统，用于评估这些相互作用对蛋白质：配体复合物形成的贡献。本文报道了在中央羟脯氨酸部分带有硫代酰胺取代的 VHL 配体的合成，并通过荧光偏振、等温滴定量热法、X 射线晶体学和分子建模来表征它们的结合。尽管结合模式保持不变，但取代模式对配体亲和力有显著影响。这些结果共同强调了氢键和 n→π 相互作用在精细调节 VHL 对羟脯氨酸的识别中的作用。
