Abstract：
RNA plays an important role in many biological processes which are crucial for cell survival, and it has been suggested that it may be possible to inhibit individual processes involved in many diseases by targeting specific sequences of RNA. The aim of this work is to determine the affinity of novel 3,9-disubstited acridine derivative 1 with three different RNA molecules, namely single stranded poly(rA), double stranded homopolymer poly(rAU) and triple stranded poly(rUAU). The results of the absorption titration assays show that the binding constant of the novel derivative to the RNA molecules was in the range of 1.7-6.2 × 104 mol dm-3. The fluorescence and circular dichroism titration assays revealed considerable changes. The most significant results in terms of interpreting the nature of the interactions were the melting temperatures of the RNA samples in complexes with the 1. In the case of poly(rA), denaturation resulted in a self-structure formation; increased stabilization was observed for poly(rAU), while the melting points of the ligand-poly(rUAU) complex showed significant destabilization as a result of the interaction. The principles of molecular mechanics were applied to propose the non-bonded interactions within the binding complex, pentariboadenylic acid and acridine ligand as the study model. Initial molecular docking provided the input structure for advanced simulation techniques. Molecular dynamics simulation and cluster analysis reveal π - π stacking and the hydrogen bonds formation as the main forces that can stabilize the binding complex. Subsequent MM-GBSA calculations showed negative binding enthalpy accompanied the complex formation and proposed the most preferred conformation of the interaction complex.
摘要：
RNA在许多对细胞生存至关重要的生物过程中发挥着重要作用。并且已经表明，通过靶向RNA的特定序列，可能抑制涉及许多疾病的个体过程。这项工作的目的是确定新的3,9-二取代吖啶衍生物1与三种不同的RNA分子的亲和力，即单链聚(rA)，双链均聚物聚(rAU)和三股聚(rUAU)。吸收滴定测定的结果表明，新型衍生物与RNA分子的结合常数在1.7-6.2×104moldm-3的范围内。荧光和圆二色性滴定测定显示出相当大的变化。就解释相互作用的性质而言，最重要的结果是与1复合物中RNA样品的解链温度。在聚（rA）的情况下，变性导致自结构形成；对于聚（rAU）观察到增加的稳定性，而配体-聚（rUAU）复合物的熔点由于相互作用而显示出显着的不稳定。应用分子力学原理提出了结合复合物内的非键合相互作用，五腺苷核糖核苷酸和吖啶配体作为研究模型。初始分子对接为高级模拟技术提供了输入结构。分子动力学模拟和聚类分析揭示了π-π堆积和氢键形成是稳定结合复合物的主要作用力。随后的MM-GBSA计算显示负结合焓伴随着复合物的形成,并提出了相互作用复合物的最优选构象。
