The sequence-based design of SMIRNAs have been developed by correlating RNA 3-dimensional folds with empirically derived interactions with small molecules. These interactions are identified via a library-versus-library selection strategy dubbed two-dimensional combinatorial screening (2DCS). Our lead identification strategy, Inforna, searches for overlap between binding partners and 3-dimensional folds in cellular RNAs, directly and quickly informing design of bioactive ligands. This approach has potential to be a general and scalable way to design bioactive ligands targeting RNA, a challenge in medicinal chemistry and chemical biology.