Efficient NMR Screening Approach to Discover Small Molecule Fragments Binding Structured RNA,ACS Medicinal Chemistry Letters

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Efficient NMR Screening Approach to Discover Small Molecule Fragments Binding Structured RNA
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2021-07-13 , DOI: 10.1021/acsmedchemlett.1c00109
Matthew D Shortridge ₁ , Gabriele Varani ₁

Affiliation

We describe a scalable nuclear magnetic resonance (NMR) screening approach to identify and prioritize small molecule fragments that bind to structured RNAs. This approach is target agnostic and, therefore, amenable to many RNA structures and libraries, and it provides initial hits for further synthetic elaboration and structure-based drug discovery efforts. We demonstrate the approach on the pre-miR-21 stem-loop, which is of significant interest in oncology and metabolic diseases. We screened the pre-miR-21 hairpin using a small (420 compounds) commercially available fragment library and identified 18 hits in the first round of triage screening. This was further refined to four fragments which passed all screening cascade filters. Among these four hits, a thiadiazole fragment was demonstrated to bind the Dicer cleavage site of pre-miR-21 by target-detected NMR experiments and through the observation of clear intermolecular NOEs.

中文翻译：

发现结合结构化 RNA 的小分子片段的高效 NMR 筛选方法

我们描述了一种可扩展的核磁共振 (NMR) 筛选方法，以识别和优先考虑与结构化 RNA 结合的小分子片段。这种方法与靶标无关，因此适用于许多 RNA 结构和文库，它为进一步的合成精细化和基于结构的药物发现工作提供了初步的成功。我们展示了 pre-miR-21 茎环的方法，这对肿瘤学和代谢疾病具有重要意义。我们使用小型（420 种化合物）市售片段库筛选了 pre-miR-21 发夹，并在第一轮分类筛选中确定了 18 个命中。这被进一步细化为通过所有筛选级联过滤器的四个片段。在这四首热门歌曲中，

更新日期：2021-08-12

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