Lundquist Kasper P, Romeo Isabella, Puglielli Raffaele B, Pestalozzi Maëlle, Gram Marie L, Hudson Emily S, Levi Ofri, Arava Yoav S, Gotfredsen Charlotte H, Clausen Mads H
DTU Chemistry, Technical University of Denmark, Kgs. Lyngby 2800, Denmark.
Faculty of Biology, Technion - Israel Institute of Technology, Haifa 3200001, Israel.
SLAS Discov. 2025 Mar;31:100215. doi: 10.1016/j.slasd.2025.100215. Epub 2025 Jan 17.
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 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.
基于片段的筛选是早期药物发现的一种有效方法。在本研究中，我们旨在创建一个针对RNA靶点产生高命中率而优化的片段库。从历史上看，RNA一直是一个未被充分探索的靶点，但最近的研究表明，优化用于RNA结合的小分子库具有潜力。我们将这一概念扩展到片段库，以产生一个RNA优化的氟化片段库。然后，我们将这个库与另外两个未针对RNA优化的片段库一起，针对三个RNA靶点进行筛选：人细胞质A位点以及有和没有核碱基修饰的酿酒酵母tRNA反密码子茎环。这些筛选分别针对各自的靶点产生了24个、31个和20个命中物。重要的是，统计分析证实了我们的RNA优化库中命中物的显著过量存在。基于这些发现，我们提出了开发RNA优化片段库的指导原则。我们希望这些指导原则将有助于加快针对RNA靶点的基于片段的配体发现，并有助于将RNA作为药物发现中有前景的靶点呈现出来。
