There is growing interest in therapeutic intervention that targets disease-relevant RNAs using small molecules. While there have been some successes in RNA-targeted small-molecule discovery, a deeper understanding of structure–activity relationships in pursuing these targets has remained elusive. One of the best-studied tertiary-structured RNAs is the theophylline aptamer, which binds theophylline with high affinity and selectivity. Although not a drug target, this aptamer has had many applications, especially pertaining to genetic control circuits. Heretofore, no compound has been shown to bind the theophylline aptamer with greater affinity than theophylline itself. However, by carrying out a high-throughput screen of low-molecular-weight compounds, several unique hits were identified that are chemically distinct from theophylline and bind with up to 340-fold greater affinity. Multiple atomic-resolution X-ray crystal structures were determined to investigate the binding mode of theophylline and four of the best hits. These structures reveal both the rigidity of the theophylline aptamer binding pocket and the opportunity for other ligands to bind more tightly in this pocket by forming additional hydrogen-bonding interactions. These results give encouragement that the same approaches to drug discovery that have been applied so successfully to proteins can also be applied to RNAs.

中文翻译：

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发现靶向三级结构 RNA 的小分子

人们越来越关注使用小分子靶向疾病相关 RNA 的治疗干预。虽然在以 RNA 为目标的小分子发现方面取得了一些成功，但在追求这些目标的过程中对结构-活性关系的更深入理解仍然难以捉摸。茶碱适体是研究最深入的三级结构 RNA 之一，它以高亲和力和选择性结合茶碱。虽然不是药物靶标，但该适体有许多应用，尤其是与遗传控制电路有关。迄今为止，还没有化合物显示出比茶碱本身以更大的亲和力结合茶碱适体。然而，通过对低分子量化合物进行高通量筛选，确定了几个独特的命中，它们在化学上不同于茶碱，并且结合亲和力高达 340 倍。确定了多个原子分辨率 X 射线晶体结构，以研究茶碱的结合模式和四个最佳命中。这些结构揭示了茶碱适体结合口袋的刚性以及其他配体通过形成额外的氢键相互作用更紧密地结合在这个口袋中的机会。这些结果令人鼓舞，已成功应用于蛋白质的相同药物发现方法也可应用于 RNA。这些结构揭示了茶碱适体结合口袋的刚性以及其他配体通过形成额外的氢键相互作用更紧密地结合在这个口袋中的机会。这些结果令人鼓舞，已成功应用于蛋白质的相同药物发现方法也可应用于 RNA。这些结构揭示了茶碱适体结合口袋的刚性以及其他配体通过形成额外的氢键相互作用更紧密地结合在这个口袋中的机会。这些结果令人鼓舞，已成功应用于蛋白质的相同药物发现方法也可应用于 RNA。