Approximately 60% of DNA is transcribed as RNA, but only 1-2% codes for proteins. There is evidence that the remaining non-coding RNA (ncRNA) is involved in the regulation or execution of cellular processes, and has been genetically linked to human diseases and traits in similar numbers as the protein-coding genes. Understanding the function of ncRNA and its interactions with small molecules will likely open up new therapeutic approaches for various diseases.<br/>To study ncRNA as a small molecule druggable target, we first investigated the use of the Automated Ligand Identification System (ALIS). ALIS is an affinity-selection MS platform capable of high-throughput screening for small-molecule binding, and has been routinely used to detect thousands of protein-small molecule interactions. We successfully adapted ALIS for detection of RNA-small molecule interactions with regulatory ncRNA bacterial riboswitches and known small molecule drug leads, and used ALIS to characterize these RNA-ligand binding events.<br/>We next identified over 40 ncRNA from a range of classes and disease areas. These ncRNA targets were screened in ALIS against chemically diverse small molecule libraries, functionally annotated libraries from phenotypic screens, and libraries enriched in RNA-binding properties (60,000+ compounds total). We have generated millions of screening data points from which we have identified new drug-like small molecules that bind to ncRNA. By further studying the structural conformation and functional consequences, we are revealing new mechanisms involving small molecule-ncRNA interactions. Here, we outline our results and discuss their implications for small-molecule drug discovery efforts.

RNA as a small molecule drug target: Discovery of selective RNA-binding small molecules by high-throughput affinity-selection mass spectrometry

256th National Meeting (2018)

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