R‑BIND 2.0: An Updated Database of Bioactive RNA-Targeting Small Molecules and Associated RNA Secondary Structures

Discoveries of RNA roles in cellular physiology and pathology are increasing the need for new tools that modulate the structure and function of these biomolecules, and small molecules are proving useful. In 2017, we curated the RNA-targeted BIoactive ligaNd Database (R-BIND) and discovered distinguishing physicochemical properties of RNA-targeting ligands, leading us to propose the existence of an “RNA-privileged” chemical space. Biennial updates of the database and the establishment of a website platform (rbind.chem.duke.edu) have provided new insights and tools to design small molecules based on the analyzed physicochemical and spatial properties. In this report and R-BIND 2.0 update, we refined the curation approach and ligand classification system as well as conducted analyses of RNA structure elements for the first time to identify new targeting strategies. Specifically, we curated and analyzed RNA target structural motifs to determine the properties of small molecules that may confer selectivity for distinct RNA secondary and tertiary structures. Additionally, we collected sequences of target structures and incorporated an RNA structure search algorithm into the website that outputs small molecules targeting similar motifs without a priori secondary structure knowledge. Cheminformatic analyses revealed that, despite the 50% increase in small molecule library size, the distinguishing properties of R-BIND ligands remained significantly different from that of proteins and are therefore still relevant to RNA-targeted probe discovery. Combined, we expect these novel insights and website features to enable the rational design of RNA-targeted ligands and to serve as a resource and inspiration for a variety of scientists interested in RNA targeting.随着RNA在细胞生理与病理过程中功能的相关研究不断深入，学界对可调控这类生物大分子结构与功能的新型工具的需求持续攀升，而小分子已被证实具备可观的应用潜力。2017年，我们完成了靶向RNA的生物活性配体数据库（RNA-targeted BIoactive ligaNd Database，简称R-BIND）的人工审编工作，并发现了RNA靶向配体所特有的理化性质，由此提出了"RNA专属化学空间（RNA-privileged chemical space）"的概念。该数据库每两年一次的更新以及配套网站平台（rbind.chem.duke.edu）的搭建，为基于已解析的理化与空间性质设计小分子配体提供了全新的研究思路与工具。在本报告及R-BIND 2.0更新版本中，我们优化了审编流程与配体分类体系，并首次针对RNA结构元件开展系统性分析，以挖掘全新的靶向策略。具体而言，我们对RNA靶点的结构基序进行了人工审编与分析，以明确可赋予小分子对不同RNA二级、三级结构选择性的关键性质。此外，我们收集了靶点结构的序列信息，并在网站中集成了RNA结构搜索算法，该算法可在无需先验二级结构知识的前提下，检索出靶向相似结构基序的小分子配体。化学信息学（Cheminformatic）分析结果显示，尽管小分子库规模扩大了50%，R-BIND收录的配体仍保持着与蛋白靶向配体显著不同的独有性质，因此该数据库依然对RNA靶向探针的开发具有重要参考价值。综上，我们期望这些全新的研究发现与网站功能，能够助力RNA靶向配体的理性设计，并为所有关注RNA靶向研究的科研人员提供宝贵的资源与研究灵感。