化工学报 ›› 2020, Vol. 71 ›› Issue (1): 344-353.DOI: 10.11949/0438-1157.20191265

• 生物化学工程与技术 • 上一篇    下一篇

异喹啉类生物碱和G-四链体结合的分子动力学研究

张博(),何依然,刘迎春,王琦()   

  1. 浙江大学化学系,浙江 杭州310027
  • 收稿日期:2019-10-24 修回日期:2019-11-07 出版日期:2020-01-05 发布日期:2020-01-05
  • 通讯作者: 王琦
  • 作者简介:张博(1993—),男,博士研究生,sour1993@zju.edu.cn
  • 基金资助:
    国家自然科学基金项目(21673206)

Molecular dynamics study of binding of isoquinoline alkaloids to G-quadruplex

Bo ZHANG(),Yiran HE,Yingchun LIU,Qi WANG()   

  1. Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang, China
  • Received:2019-10-24 Revised:2019-11-07 Online:2020-01-05 Published:2020-01-05
  • Contact: Qi WANG

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

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

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