Department of Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, Guangdong, China.
RNA Biol. 2023 Jan;20(1):431-443. doi: 10.1080/15476286.2023.2231708.
Recent studies suggest RNAs act as promising drug targets. However, limited development has been achieved in detecting RNA-ligand interactions. To guide the discovery of RNA-binding ligands, it is necessary to characterize them comprehensively, especially in the binding specificity, binding affinity and drug-like properties. We established a database, RNALID (http://biomed.nscc-gz.cn/RNALID/html/index.html#/database), which collects RNA-ligand interactions validated by low-throughput experiment. RNALID contains 358 RNA-ligand interactions. Comparing to the fellow database, 94.5% of ligands in RNALID are completely or partially novel collections, and 51.78% have novel two-dimensional (2D) structures. Through the analysis of ligand structure, binding affinity and cheminformatic parameters we found that multivalent (MV) ligands mainly binding to RNA repeats are more structurally conserved in both 2D and 3D structures than other ligand types, exhibit higher binding specificity and binding affinity than ligands binding to non-repeat RNAs, but deviate far from the Lipinski's rule of five. In contrary, small molecule (SM) ligands binding to virus RNA exhibit higher affinity and more resemble protein-ligands, but potentially possess low binding specificity. Further analysis on 28 detailed drug-likeness properties indicated that RNA-ligands' development need to balance between the binding affinity and the drug-likeness because of the significant linear co-relationship between the two. Comparing RNALID ligands to FDA-approved drugs and ligands without bioactivity indicated that RNA-binding ligands are different from them in chemical properties, structural properties and drug-likeness. Thus, characterizing the RNA-ligand interactions in RNALID in multiple respects provides new insights into discovering and designing druggable ligands binding with RNA.
最近的研究表明，RNA 可以作为有前途的药物靶点。然而，在检测 RNA-配体相互作用方面的发展有限。为了指导 RNA 结合配体的发现，有必要全面地描述它们，特别是在结合特异性、结合亲和力和类药性方面。我们建立了一个数据库，RNALID（http://biomed.nscc-gz.cn/RNALID/html/index.html#/database），其中收集了经过低通量实验验证的 RNA-配体相互作用。RNALID 包含 358 个 RNA-配体相互作用。与同类数据库相比，RNALID 中的 94.5%的配体是完全或部分新颖的集合，51.78%具有新颖的二维（2D）结构。通过对配体结构、结合亲和力和化学信息学参数的分析，我们发现多价（MV）配体主要与 RNA 重复结合，在 2D 和 3D 结构中比其他配体类型更具结构保守性，与非重复 RNA 结合的配体相比，具有更高的结合特异性和结合亲和力，但远偏离了 Lipinski 的五规则。相反，与病毒 RNA 结合的小分子（SM）配体表现出更高的亲和力，更类似于蛋白质-配体，但可能具有较低的结合特异性。对 28 个详细的类药性特性的进一步分析表明，由于两者之间存在显著的线性相关性，RNA 配体的开发需要在结合亲和力和类药性之间取得平衡。将 RNALID 配体与 FDA 批准的药物和无生物活性的配体进行比较表明，RNA 结合配体在化学性质、结构性质和类药性方面与它们不同。因此，从多个方面描述 RNALID 中的 RNA-配体相互作用，为发现和设计与 RNA 结合的可成药性配体提供了新的见解。
