Insights into the development of chemical probes for RNA

Morgan, Brittany S; Forte, Jordan E; Hargrove, Amanda E

Hit rates are one of the benchmarks used to assess the efficiency of a screen. We note prior to the discussion that comparisons across studies should be interpreted with caution as the definition of a small molecule lead, the specific assays used in primary screens, the controls utilized in the assay, and the number of false-positives and -negatives can be highly variable and are not always reported. Of the 41 RNA:small molecule interactions discovered through HTS and FcS, 20 had reported hit rates, which were compared by screening approach, primary screen, and primary library [ Figure 3 ]. The higher hit rates found in some FcS approaches provide compelling evidence that FcS is efficient for RNA targets, as it is known to be for protein targets (35, 36) . Moving forward, characterization of additional RNA tertiary structures (8, 9, 37, 38) and the identification of novel RNA-binding chemotypes (8, 39, 40) will expedite the FcS approach for discovering biologically active RNA-targeted ligands. While hit rates varied widely within each type of primary screen and primary library, these com-parisons support the potential of many distinct paths toward RNA ligand discovery. Specific aspects of library and screen design are discussed below.