Appavoo Solomon D, Heller Nicholas W, van Campenhout Christian T, Saunders George J, Yudin Andrei K
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada, M5S 3H6.
Angew Chem Int Ed Engl. 2024 Jul 8;63(28):e202402372. doi: 10.1002/anie.202402372. Epub 2024 Jun 6.
While peptide macrocycles with rigidified conformations have proven to be useful in the design of chemical probes of protein targets, conformational flexibility and rapid interconversion can be equally vital for biological activity and favorable physicochemical properties. This study introduces the concept of "structural pin", which describes a hydrogen bond that is largely responsible for stabilizing the entire macrocycle backbone conformation. Structural analysis of macrocycles using nuclear magnetic resonance (NMR), molecular modelling and X-ray diffraction indicates that disruption of the structural pin can drastically influence the conformation of the entire ring, resulting in novel states with increased flexibility. This finding provides a new tool to interrogate dynamic behaviour of macrocycles. Identification of structural pins offers a useful conceptual framework to understand positions that can either be modified to give flexible structures or retained to maintain the rigidity of the scaffold.
虽然具有刚性构象的肽大环已被证明在蛋白质靶点化学探针的设计中很有用，但构象灵活性和快速相互转化对于生物活性和良好的物理化学性质同样至关重要。本研究引入了“结构钉”的概念，它描述了一种氢键，这种氢键在很大程度上负责稳定整个大环骨架构象。使用核磁共振（NMR）、分子建模和X射线衍射对大环进行结构分析表明，结构钉的破坏会极大地影响整个环的构象，从而产生具有更高灵活性的新状态。这一发现为研究大环的动态行为提供了一种新工具。结构钉的识别提供了一个有用的概念框架，以理解既可以进行修饰以产生灵活结构，也可以保留以维持支架刚性的位置。
