Wicks Sarah L, Morgan Brittany S, Wilson Alexander W, Hargrove Amanda E
Department of Chemistry; Duke University; 124 Science Drive; Durham, NC 27708.
Department of Chemistry & Biochemistry; University of Notre Dame; 123 McCourtney Hall Notre Dame, IN 46556.
bioRxiv. 2023 Jul 31:2023.07.31.551350. doi: 10.1101/2023.07.31.551350.
Small molecules have become increasingly recognized as invaluable tools to study RNA structure and function and to develop RNA-targeted therapeutics. To rationally design RNA-targeting ligands, a comprehensive understanding and explicit testing of small molecule properties that govern molecular recognition is crucial. To date, most studies have primarily evaluated properties of small molecules that bind RNA , with little to no assessment of properties that are distinct to selective and bioactive RNA-targeted ligands. Therefore, we curated an RNA-focused library, termed the Duke RNA-Targeted Library (DRTL), that was biased towards the physicochemical and structural properties of biologically active and non-ribosomal RNA-targeted small molecules. The DRTL represents one of the largest academic RNA-focused small molecule libraries curated to date with more than 800 small molecules. These ligands were selected using computational approaches that measure similarity to known bioactive RNA ligands and that diversify the molecules within this space. We evaluated DRTL binding to a panel of four RNAs using two optimized fluorescent indicator displacement assays, and we successfully identified multiple small molecule hits, including several novel scaffolds for RNA. The DRTL has and will continue to provide insights into biologically relevant RNA chemical space, such as the identification of additional RNA-privileged scaffolds and validation of RNA-privileged molecular features. Future DRTL screening will focus on expanding both the targets and assays used, and we welcome collaboration from the scientific community. We envision that the DRTL will be a valuable resource for the discovery of RNA-targeted chemical probes and therapeutic leads.
小分子已日益被视为研究RNA结构与功能以及开发RNA靶向疗法的宝贵工具。为了合理设计RNA靶向配体，全面了解并明确测试决定分子识别的小分子特性至关重要。迄今为止，大多数研究主要评估了与RNA结合的小分子特性，而对选择性和生物活性RNA靶向配体特有的特性几乎没有评估。因此，我们精心构建了一个以RNA为重点的文库，称为杜克RNA靶向文库（DRTL），该文库偏向于生物活性和非核糖体RNA靶向小分子的物理化学和结构特性。DRTL是迄今为止精心构建的最大的学术性以RNA为重点的小分子文库之一，包含800多种小分子。这些配体是使用计算方法选择的，这些方法测量与已知生物活性RNA配体的相似性，并使该空间内的分子多样化。我们使用两种优化的荧光指示剂置换分析法评估了DRTL与一组四种RNA的结合情况，并成功鉴定出多个小分子命中物，包括几种新型的RNA支架。DRTL已经并将继续为生物学相关的RNA化学空间提供见解，例如识别更多的RNA特权支架和验证RNA特权分子特征。未来的DRTL筛选将集中于扩大所使用的靶点和分析方法，我们欢迎科学界的合作。我们设想DRTL将成为发现RNA靶向化学探针和治疗先导物的宝贵资源。
