Gober Isaiah N, Waters Marcey L
Department of Chemistry, CB 3290, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Org Biomol Chem. 2017 Sep 26;15(37):7789-7795. doi: 10.1039/c7ob01921a.
In the design of small molecule receptors for polar guests, much inspiration has been taken from proteins that have adapted effective ways to selectively bind polar molecules in aqueous environments. Nonetheless, molecular recognition of hydrophilic guests in water by synthetic receptors remains a challenging task. Here we report a new synthetic receptor, A2I, with improved affinity and selectivity for a biologically important polar guest, dimethyllysine (Kme2). A2I was prepared via redesign of a small molecule receptor (A2B) that preferentially binds trimethyllysine (Kme3) using dynamic combinatorial chemistry (DCC). We designed a new biphenyl-2,6-dicarboxylate monomer, I, with the goal of creating a buried salt bridge with Kme2 inside a synthetic receptor. Indeed, incorporation of I into the receptor A2I resulted in a receptor with 32-fold enhancement in binding affinity, which represents the highest affinity receptor for Kme2 in the context of a peptide to date and is tighter than most Kme2 reader proteins. It also exhibits a ∼2.5-fold increase in preference for Kme2 vs. Kme3 relative to the parent receptor, A2B. This work provides insight into effective strategies for binding hydrophilic, cationic guests in water and is an encouraging result toward a synthetic receptor that selectively binds Kme2 over other methylation states of lysine.
在设计用于极性客体的小分子受体时，人们从蛋白质中获得了很多灵感，这些蛋白质采用了有效的方式在水性环境中选择性结合极性分子。尽管如此，合成受体在水中对亲水性客体的分子识别仍然是一项具有挑战性的任务。在此，我们报告一种新型合成受体A2I，它对一种具有生物学重要性的极性客体二甲基赖氨酸（Kme2）具有更高的亲和力和选择性。A2I是通过使用动态组合化学（DCC）对优先结合三甲基赖氨酸（Kme3）的小分子受体（A2B）进行重新设计而制备的。我们设计了一种新的联苯 - 2,6 - 二羧酸酯单体I，目的是在合成受体内与Kme2形成一个埋藏的盐桥。事实上，将I掺入受体A2I中得到了一种结合亲和力提高32倍的受体，这是迄今为止在肽的背景下对Kme2具有最高亲和力的受体，并且比大多数Kme2识别蛋白的结合更紧密。相对于亲本受体A2B，它对Kme2与Kme3的选择性也提高了约2.5倍。这项工作为在水中结合亲水性阳离子客体的有效策略提供了见解，并且朝着一种能够选择性结合Kme2而非赖氨酸其他甲基化状态的合成受体迈出了令人鼓舞的一步。
