Design and Implementation of an Ribonucleic Acid (RNA) Directed Fragment Library
Design and Implementation of an Ribonucleic Acid (RNA) Directed Fragment Library
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DOI：
10.1021/jm9000659
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发表时间：
2009-06-25
影响因子：
7.3
通讯作者：
Aboul-ela, Fareed
中科院分区：
文献类型：
--
作者：
Bodoor, Khaled;Boyapati, Vamsi;Aboul-ela, Fareed
RNA结合配体的设计由于特异性、靶点灵活性和已知RNA抑制剂对化学衍生化的易处理性的问题而变得复杂。为了解决这些困难，RNA定向片段化合物库。我们首先分析了120种具有RNA结合活性的小分子。计算的RNA配体的物理和化学性质与已建立的蛋白质药物靶标的配体的物理和化学性质相当。为了确保我们的文库包含可能无法通过上述比较检测到的RNA结合功能，基于与RNA配体的亚结构的相似性购买了114个片段化合物。通过NMR鉴定了来自细菌核糖体的解码位点的五个“命中”。这些包括衍生自A位点结合配体的片段，但也包括先前未鉴定为A位点结合剂的化合物。以这种方式产生的命中可以用于探测RNA的相互作用表面及其构象可塑性，促进基于结构的优化。
The design of RNA binding ligands is complicated by issues of specificity, target flexibility, and the tractability of known RNA inhibitors toward chemical derivitization. To address these difficulties, an RNA-directed fragment compound library is presented. We began with an analysis of 120 small molecules with reported RNA-binding activity. Calculated physical and chemical properties for the RNA ligands are comparable to those of ligands for established protein drug targets. To ensure that our library contained RNA-binding functionalities that might not be detected by the above comparisons, 114 fragment compounds were purchased on the basis of similarity to substructures of RNA ligands. Five "hits" were identified for the decoding site from the bacterial ribosome by NMR. These included fragments derived from A-site binding ligands but also compounds not previously identified as A-site binders. Hits generated in this manner can be used to probe the interaction surface of RNA and its conformational plasticity, facilitating structure-based optimization.