Abstract:

G-quadruplex is a nonclassical secondary structure of nucleic acids, which is mainly found in guanine (G) - rich DNA or RNA sequences. The G-quadruplex in organism is mainly formed in the telomere region and the promoter region of some proto-oncogenes, which is an essential object of biomedical research. Although the anti-cancer strategy targeting G-quadruplex has been proposed many times, no successful clinical trials have been conducted so far. Therefore, the study of G-quadruplex ligand binding in the proto-oncogene promoter region can provide guiding suggestions for the design of targeted anti-cancer drugs. The binding mechanism of different isoquinoline alkaloids to G-quadruplex was studied by molecular dynamics simulation. The confirmation of the stable binding of four isoquinoline ligands to G-quadruplex and the dominant factors of the binding were obtained by studying the binding process of the four isoquinoline ligands to G-quadruplex. This work has deepened the microscopic understanding of the binding mechanism of isoquinoline alkaloids and G-quadruplex at the atomic and molecular level and has guiding significance for the design of anti-cancer drugs.

Key words: molecular simulation, G-quadruplex, isoquinoline alkaloids, binding mechanics, design of anti-cancer drugs, DNA, computational chemistry

摘要：

G-四链体是核酸的一种非经典二级结构，主要出现于富含鸟嘌呤（G）碱基的DNA或RNA序列。生物体内的G-四链体主要形成于端粒区域和某些原癌基因的启动子区域，是生物医学研究的重要对象。以G-四链体作为靶点的抗癌策略虽被多次提出，但目前还未有成功进入临床试验的案例。因此，有关原癌基因启动子区域的G-四链体与配体结合的研究，可以对靶向抗癌药物的设计提供指导性建议。使用分子动力学模拟的方法，研究了不同的异喹啉类生物碱与G-四链体的结合机理。通过考察四种异喹啉配体与G-四链体结合的过程，得到了异喹啉配体与G-四链体稳定结合的构象以及结合的主导因素。此工作从原子分子层面深化了对异喹啉类生物碱和G-四链体结合机理的微观认识，对抗癌药物设计具有指导意义。

关键词: 分子模拟, G-四链体, 异喹啉类生物碱, 结合机理, 抗癌药物设计, 脱氧核糖核酸, 计算化学