New derivatives of aminoglycosides containing 6′-carboxylic acid or 6′-amide on their ring I were designed, synthesized and their ability to readthrough nonsense mutations was examined in vitro, along with the protein translation inhibition in prokaryotic and eukaryotic systems. The observed structure–activity relationships, along with the comparative molecular dynamics simulations within the eukaryotic rRNA decoding site, showed high sensitivity of 6′-position to substitution, indicating that the rational design of potent stop-codon read-through inducers requires consideration of not only the structure and energetics of the drug–RNA interaction but also the dynamics associated with that interaction.

中文翻译：

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用氨基糖苷衍生物探索真核与原核核糖体 RNA 识别†

设计、合成了在其环 I 上含有 6'-羧酸或 6'-酰胺的氨基糖苷类的新衍生物，并在体外检测了它们读取无义突变的能力，以及在原核和真核系统中的蛋白质翻译抑制。观察到的结构-活性关系，以及真核 rRNA 解码位点内的比较分子动力学模拟，显示出 6' 位对取代的高度敏感性，表明有效的终止密码子通读诱导剂的合理设计需要考虑不只有药物-RNA相互作用的结构和能量学，还有与这种相互作用相关的动力学。