Computer-aided design of RNA-targeted small molecules: A growing need in drug discovery

In recent years, researchers have identified certain RNAs as druggable targets for small molecules to treat several human pathologies. However, these regulatory RNAs are challenging targets due to their intrinsic structural flexibility and poorly characterized structure-function relationships. Standard drug-discovery approaches have therefore been adjusted to identify and optimize RNA-targeted small molecules. In this context, our review first outlines the regulatory RNAs that have been structurally and functionally characterized and identified as druggable targets for small molecules. Using representative case studies, we then critically examine the power and challenges of molecular modeling, docking, and simulations and the synergistic interconnection of computational tools with experimental methods for RNA-targeted structure-based drug design.