吲哚并喹啉衍生物与G-四链体相互作用的分子模拟研究

Molecular Modeling Studies of Interactions between Quindoline Derivatives and G-quadruplex

G-四链体是富含鸟嘌呤碱基的DNA序列通过氢键相互作用形成的四链螺旋结构.通过小分子化合物诱导与稳定端粒G-四链体从而抑制端粒酶活性是一种新的抗癌策略.为了研究一系列吲哚并喹啉衍生物与端粒G-四链体的相互作用,探究其相互作用模式,从而为实现基于G-四链体结构的药物合理设计提供依据,使用分子对接的方法构建了吲哚并喹啉衍生物与G-四链体复合物结构,在此基础上进行分子动力学模拟,并使用线性相互作用能(LIE)方法计算了化合物与G-四链体的结合自由能.结果表明:化合物与G-四链体的主要相互作用方式由氢键、静电与π-π堆积作用构成,侧链末端基团类型和侧链的长短是影响相互作用强弱的重要因素.通过LIE方法计算的结合自由能与实验结果基本吻合,相关度达到r2=0.79.并且,基于预测的结合模式,总结了拥有更高活性的新型吲哚并喹啉衍生物应具有的几个结构特征.

G-quadruplex is a four stranded quadruplex drogen bonds. Inhibition of telomerase by organic structure in G-rich DNA sequence formed by hycompounds that can induce and stabilize the G-quadruplex structure is merging as a new anti-cancer strategy. This article discusses the interaction and binding mode between a series of quindoline derivatives and telomeric G-quadruplex, which may serve as basis of rational design of drugs targeting the G-quadruplex. The interactions of compounds with human te- lomeric G-quadruplex were simulated by molecular docking and molecular dynamics simulations and their binding free energies were evaluated by a linear interaction energy method. Results showed that the binding of quindoline derivatives and G-quadruplex was maintained by hydrogen bond, aromatic π-π stacking, and electrostatic interactions. Terminal substituted groups and length of the side chains are important factors that influence the potency. The predicted binding free energies well correlate the experimental results with r2= 0.79. Based on the predicted binding mode, features of the compounds with higher biological activity were summarized at the end of this article.