Design, synthesis, and screening of an RNA optimized fluorinated fragment library

Fragment-based screening is an efficient method for early-stage drug discovery. In this study, we aimed to create a fragment library optimized for producing high hit rates against RNA targets. RNA has historically been an underexplored target, but recent research suggests potential for optimizing small molecule libraries for RNA binding. We extended this concept to fragment libraries to produce an RNA optimized fluorinated fragment library. We then screened this library, alongside two non-RNA optimized fragment libraries, against three RNA targets: the human cytoplasmic A-site and the S. cerevisiae tRNA^Asp anticodon stem loop with and without nucleobase modifications. The screens yielded 24, 31, and 20 hits against the respective targets. Importantly, statistical analysis confirmed a significant overrepresentation of hits in our RNA optimized library. Based on these findings, we propose guidelines for developing RNA optimized fragment libraries. We hope the guidelines will help expediting fragment-based ligand discovery for RNA targets and contribute to presenting RNA as a promising target in drug discovery.