Discovery of Key Physicochemical, Structural, and Spatial Properties of RNA‐Targeted Bioactive Ligands

Abstract While a myriad non‐coding RNAs are known to be essential in cellular processes and misregulated in diseases, the development of RNA‐targeted small molecule probes has met with limited success. To elucidate the guiding principles for selective small molecule/RNA recognition, we analyzed cheminformatic and shape‐based descriptors for 104 RNA‐targeted ligands with demonstrated biological activity (RNA‐targeted BIoactive ligaNd Database, R‐BIND). We then compared R‐BIND to both FDA‐approved small molecule drugs and RNA ligands without reported bioactivity. Several striking trends emerged for bioactive RNA ligands, including: 1) Compliance to medicinal chemistry rules, 2) distinctive structural features, and 3) enrichment in rod‐like shapes over others. This work provides unique insights that directly facilitate the selection and synthesis of RNA‐targeted libraries with the goal of efficiently identifying selective small molecule ligands for therapeutically relevant RNAs.