Metal ions play important roles in protein and RNA structure and function and the construction of ligands frequently focuses on the exploitation of functionality designed to engage a metal. However, there are circumstances where functionality can be incorporated into a ligand to emulate the metal ion, allowing target engagement by displacing or replacing the metal and directly interacting with the metal-binding elements in the target. In this Digest, we illustrate protein and RNA modulators that exploit this design principle, with all of the examples based on the displacement or replacement of a magnesium ion, and which can confer a potency advantage. Moreover, this approach relies upon an inversion of the physical chemical properties of a more conventional metal-binding ligand.

金属离子在蛋白质和RNA的结构和功能中起着重要的作用，配体的构建通常集中在开发旨在与金属结合的功能上。但是，在某些情况下，可以将官能团结合到配体中以模拟金属离子，从而通过置换或替代金属并与靶中的金属结合元素直接相互作用来实现靶的结合。在本摘要中，我们说明了利用该设计原理的蛋白质和RNA调节剂，所有示例均基于镁离子的置换或置换，并且可以带来效价优势。而且，该方法依赖于更常规的金属结合配体的物理化学性质的反转。