Fragment-based ligand discovery for RNA targets

Fragment-based ligand discovery is a promising method for early-stage drug discovery. In this project, I aimed to develop a fragment library optimized for producing high hit rates against RNA targets. RNA has historically been an underexplored target, but recent research suggests that small molecule libraries can be optimized for RNA binding. I extended this concept to develop an RNA optimized fluorinated fragment library.
I then screened this library, as well as two non-RNA optimized fragment libraries, against four 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, 37, and 24 hits respectively. I also screened one of the non-RNA optimized fragment libraries against the prokaryotic FMN riboswitch RNA target, yielding three hits.
Statistical analysis of the hit rates confirmed a significant overrepresentation of hits in the RNA optimized library. I propose guidelines for producing RNA optimized fragment libraries based on these findings. I hope the guidelines may further support the current efforts for fragment-based ligand discovery against RNA targets.