Department of Chemistry and the Center of Excellence in Bioinformatics and Life Sciences, The University at Buffalo, The State University of New York, 657 Natural Sciences Complex, Buffalo, New York 14260, United States.
ACS Chem Biol. 2012 Nov 16;7(11):1902-9. doi: 10.1021/cb300213g. Epub 2012 Sep 14.
There are many potential RNA drug targets in bacterial, viral, and human transcriptomes. However, there are few small molecules that modulate RNA function. This is due, in part, to a lack of fundamental understanding about RNA-ligand interactions including the types of small molecules that bind to RNA structural elements and the RNA structural elements that bind to small molecules. In an effort to better understand RNA-ligand interactions, we diversified the 2-aminobenzimidazole core (2AB) and probed the resulting library for binding to a library of RNA internal loops. We chose the 2AB core for these studies because it is a privileged scaffold for binding RNA based on previous reports. These studies identified that N-methyl pyrrolidine, imidazole, and propylamine diversity elements at the R1 position increase binding to internal loops; variability at the R2 position is well tolerated. The preferred RNA loop space was also determined for five ligands using a statistical approach and identified trends that lead to selective recognition.
细菌、病毒和人类转录组中有许多潜在的 RNA 药物靶点。然而，能够调节 RNA 功能的小分子却寥寥无几。这在一定程度上是由于人们对 RNA-配体相互作用的基本原理缺乏了解，包括与 RNA 结构元件结合的小分子的种类以及与小分子结合的 RNA 结构元件。为了更好地了解 RNA-配体相互作用，我们对 2-氨基苯并咪唑核心（2AB）进行了多样化处理，并研究了该文库与 RNA 内部环文库的结合情况。我们之所以选择 2AB 核心进行这些研究，是因为根据以往的报告，它是一种结合 RNA 的优势支架。这些研究表明，R1 位置的 N-甲基吡咯烷、咪唑和丙胺多样性元件可增加与内部环的结合；R2 位置的可变性可被很好地耐受。还使用统计方法确定了五个配体的首选 RNA 环空间，并确定了导致选择性识别的趋势。
