Martín-Villamil María, Sanmartín Isaías, Moreno Ángela, Gallego José
Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, C/Quevedo 2, 46001 Valencia, Spain.
Pharmaceuticals (Basel). 2022 Jun 14;15(6):748. doi: 10.3390/ph15060748.
New RNA-binding small-molecule scaffolds are needed to unleash the pharmacological potential of RNA targets. Here we have applied a pharmacophore-based virtual screening approach, seldom used in the RNA recognition field, to identify novel conformational inhibitors of the hepatitis C virus internal ribosome entry site. The conformational effect of the screening hits was assessed with a fluorescence resonance energy transfer assay, and the affinity, specificity, and binding site of the ligands were determined using a combination of fluorescence intensity and NMR spectroscopy experiments. The results indicate that this strategy can be successfully applied to discover RNA conformational inhibitors bearing substantially less positive charge than the reference ligands. This methodology can potentially be accommodated to other RNA motifs of pharmacological interest, facilitating the discovery of novel RNA-targeted molecules.
需要新的RNA结合小分子支架来释放RNA靶点的药理学潜力。在这里，我们应用了一种基于药效团的虚拟筛选方法（该方法在RNA识别领域很少使用）来鉴定丙型肝炎病毒内部核糖体进入位点的新型构象抑制剂。通过荧光共振能量转移测定法评估筛选命中物的构象效应，并使用荧光强度和核磁共振光谱实验相结合的方法确定配体的亲和力、特异性和结合位点。结果表明，该策略可成功应用于发现比参考配体带正电荷少得多的RNA构象抑制剂。这种方法有可能适用于其他具有药理学意义的RNA基序，有助于发现新型RNA靶向分子。
