Discovery of RNA-targeted small molecules through the merging of experimental and computational technologies

The field of RNA-targeted small molecules is rapidly evolving, owing to the advances in experimental and computational technologies. With the identification of several bioactive small molecules that target RNA, including the FDA-approved risdiplam, the biopharmaceutical industry is gaining confidence in the field. This review, based on the literature obtained from PubMed, aims to disseminate information about the various technologies developed for targeting RNA with small molecules and propose areas for improvement to develop drugs more efficiently, particularly those linked to diseases with unmet medical needs.

The technologies for the identification of RNA targets, screening of chemical libraries against RNA, assessing the bioactivity and target engagement of the hit compounds, structure determination, and hit-to-lead optimization are reviewed. Along with the description of the technologies, their strengths, limitations, and examples of how they can impact drug discovery are provided.

Many existing technologies employed for protein targets have been repurposed for use in the discovery of RNA-targeted small molecules. In addition, technologies tailored for RNA targets have been developed. Nevertheless, more improvements are necessary, such as artificial intelligence to dissect important RNA structures and RNA-small-molecule interactions and more powerful chemical probing and structure prediction techniques.