核糖核酸
化学
碱基对
计算生物学
化学信息学
小分子
核糖体
非编码RNA
核糖体RNA
DNA
分子
生物化学
基因
生物
计算化学
有机化学
作者
Hafeez S. Haniff,Amanda B. Graves,Matthew D. Disney
标识
DOI:10.1021/acscombsci.8b00049
摘要
Many types of RNAs exist in the human transcriptome, yet only the bacterial ribosome has been exploited as a small molecule drug target. Aside from rRNA, other cellular RNAs such as noncoding RNAs have primarily secondary structure and limited tertiary structure. Within these secondary structures of noncanonically paired and unpaired regions, more than 50% are base paired, with most efforts to target these structures focused on looped regions. A void exists in the availability of small molecules capable of targeting RNA base pairs. Using chemoinformatics, an RNA-focused library enriched for nitrogen-containing heterocycles was developed and tested for binding RNA base pairs, leading to the identification of six selective and previously unknown binders. While all binders were derivatives of benzimidazoles, those with expanded aromatic polycycles bound selectively to AU pairs, while those with flexible urea side chains bound selectively to GC pairs. Two of the three selective GC pair binders can distinguish between two different orientations, 5′GG/3′CC and 5′GC/3′CG pairs. Furthermore, all six molecules showed >50-fold selectivity for RNA over DNA. These studies provide foundational knowledge to better exploit RNA as targets for small molecule chemical probes or lead therapeutics by using modules that target RNA base pairs.
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