异喹啉类生物碱和G-四链体结合的分子动力学研究

doi:10.11949/0438-1157.20191265

摘要/Abstract

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

中图分类号:

O 641.3

张博, 何依然, 刘迎春, 王琦. 异喹啉类生物碱和G-四链体结合的分子动力学研究[J]. 化工学报, 2020, 71(1): 344-353.

Bo ZHANG, Yiran HE, Yingchun LIU, Qi WANG. Molecular dynamics study of binding of isoquinoline alkaloids to G-quadruplex[J]. CIESC Journal, 2020, 71(1): 344-353.

图/表 16

图1 G平面中的Hoogsteen配对

Fig.1 Hoogsteen pairing in G-quartet

表1 本工作选取的四种异喹啉类生物碱

Table 1 Four isoquinoline alkaloids selected in this work

常用名	英文名	缩写	分子式
血根碱^[18]	Sanguinarine	SAU	C₂₀H₁₄NO₄⁺
二氢血根碱^[19]	Dihydrosanguinarine	DHS	C₂₀H₁₅NO₄
南天宁碱^[20]	Nantenine	NAT	C₂₀H₂₁NO₄
白屈菜碱^[21]	Chelidonine	CHL	C₂₀H₁₉NO₅

图2 四种异喹啉类生物碱的分子结构

Fig.2 Molecular structure of four isoquinoline alkaloids

图3 四种异喹啉配体和G-四链体的相互作用能

Fig.3 Interaction energy of four isoquinoline ligands and G-quadruplex

图4 异喹啉配体在G-四链体上的四个结合区域

Fig.4 Four binding regions of isoquinoline ligand on G-quadruplex

图5 配体结合在四种位点上的概率

Fig.5 Probability of ligand binding at four sites

图6 四个结合位点和相应配体的相互作用能

Fig.6 Interaction energies of four binding sites and corresponding ligands

图7 四种异喹啉配体和G平面的结合构象

Fig.7 Binding conformation of four isoquinoline ligands and G-quartet

图8 异喹啉配体和G平面上各个碱基的相互作用能

Fig.8 Interaction energy between isoquinoline ligands and each base on G-quartet

图9 白屈菜碱及设计配体构象

Fig.9 Conformation of CHL and designed ligands

图10 Z01与G平面的结合构象

Fig.10 Conformation of Z01 bound to G-quartet

图11 模拟过程中G平面结构变化示意图A—键角；B—键长；D—二面角

Fig.11 Schematic diagram of G-quartet structure changes during simulation

图12 与Z01结合过程中G-平面四个碱基相互作用能变化示意图

Fig.12 Schematic diagram of interaction energy change of four bases in G-quartet during binding with Z01

图13 血根碱在G平面上结合的两种结合构型

Fig.13 Two configuration of SAU binding with G-quartet

图14 两种结合构型中G-四链体不同部分的作用能比较

Fig.14 Comparison of action energies of different parts of G-quadruplex in two binding configurations

图15 构型B中5'端各个碱基对血根碱的作用

Fig.15 Interaction of 5' terminal bases on SAU in configuration B

参考文献 32

1	Simonsson T. G-Quadruplex DNA structures — variations on a theme[J]. Biological Chemistry, 2001, 382(4): 621-628.
2	Brooks T A, Hurley L H. The role of supercoiling in transcriptional control of MYC and its importance in molecular therapeutics[J]. Nature Reviews Cancer, 2009, 9(12): 849-861.
3	Mathad R I, Hatzakis E, Dai J, et al. c-MYC promoter G-quadruplex formed at the 5'-end of NHE III1 element: insights into biological relevance and parallel-stranded G-quadruplex stability[J]. Nucleic Acids Research, 2011, 39(20): 9023-9033.
4	Dang C V. MYC on the path to cancer[J]. Cell, 2012, 149(1): 22-35.
5	Wahlstrom T, Henriksson M. Impact of MYC in regulation of tumor cell metabolism[J]. Biochimica et Biophysica Acta, 2015, 1849(5): 563-569.
6	汤慧敏, 李玉峰. C-myc在慢性髓系白血病中的作用机制研究进展[J].中国实验血液学杂志, 2019, 27(1): 297-300.
	Tang H M, Li Y F. Research progress of C-myc in chronic myelogenous leukemia[J]. J. Exp. Hematol., 2019, 27(1): 297-300.
7	杜清, 杨巧红, 张新江, 等. C-myc在胃癌治疗方面的研究进展[J].转化医学电子杂志, 2018, 5(9): 53-58.
	Du Q, Yang Q H, Zhang X J, et al. Research progress of C-myc in the treatment of gastric cancer[J].E-Journal of Translational Medicine, 2018, 5(9): 53-58.
8	吴飞翔, 曹骥, 赵荫农, 等. B-myb C-myc在肝细胞性肝癌中的表达及临床意义[J].中国肿瘤临床, 2008, (5): 269-271+276.
	Wu F X, Cao J, Zhao Y N, et al. Expression of B-myb and C-myc in hepatocellular carcinoma and its clinical significance[J]. Chin. J. Clin. Oncol., 2008, (5): 269-271+276.
9	宋春丽, 呼君瑜, 李美艳, 等. FHIT、C-myc在宫颈癌中的表达及其与高危型HPV感染的相关性[J].中国肿瘤, 2016, 25(5): 395-399.
	Song C L, Hu J Y, Li M Y, et al. Expression of FHIT and C-myc in cervical cancer and its correlation with high-risk HPV infection[J]. China Cancer, 2016, 25(5): 395-399.
10	Xiong Y, Huang Z, Tan J, et al. Targeting G-quadruplex nucleic acids with heterocyclic alkaloids and their derivatives[J]. European Journal of Medicinal Chemistry, 2015, 97: 538-551.
11	Ma Y, Ou T, Hou J, et al. 9-N-Substituted berberine derivatives: stabilization of G-quadruplex DNA and down-regulation of oncogene C-myc[J]. Bioorganic & Medicinal Chemistry, 2008, 16(16): 7582-7591.
12	Shen H, Zhang B, Xu H, et al. Microfluidic-based G-quadruplex ligand displacement assay for alkaloid anticancer drug screening[J]. Journal of Pharmaceutical and Biomedical Analysis, 2017, 134: 333-339.
13	Luo D, Mu Y. All-atomic simulations on human telomeric G-quadruplex DNA binding with thioflavin T[J]. Journal of Physical Chemistry B, 2015, 119(15): 4955-4967.
14	Verma S, Ghuge S A, Ravichandiran V, et al. Spectroscopic studies of thioflavin-T binding to c-Myc G-quadruplex DNA[J]. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2019, 212: 388-395.
15	Li Q, Xiang J, Li X, et al. Stabilizing parallel G-quadruplex DNA by a new class of ligands: two non-planar alkaloids through interaction in lateral grooves[J]. Biochimie, 2009, 91(7): 811-819.
16	Li J, Jin X, Hu L, et al. Identification of nonplanar small molecule for G-quadruplex grooves: molecular docking and molecular dynamic study[J]. Bioorganic & Medicinal Chemistry Letters, 2011, 21(23): 6969-6972.
17	Huang S, Liang Y, Cui J, et al. Comparative investigation of binding interactions with three steroidal derivatives of d(GGGT)₄ G-quadruplex aptamer[J]. Steroids, 2018, 132: 46-55.
18	Bessi I, Bazzicalupi C, Richter C, et al. Spectroscopic, molecular modeling, and NMR-spectroscopic investigation of the binding mode of the natural alkaloids berberine and sanguinarine to human telomeric G-quadruplex DNA[J]. ACS Chemical Biology, 2012, 7(6): 1109-1119.
19	Psotova J, Klejdus B, Vecera R, et al. A liquid chromatographic-mass spectrometric evidence of dihydrosanguinarine as a first metabolite of sanguinarine transformation in rat[J]. Journal of Chromatography B, 2006, 830(1): 165-172.
20	Indra B, Matsunaga K, Hoshino O, et al. Structure–activity relationship studies with (±)-nantenine derivatives for α1-adrenoceptor antagonist activity[J]. European Journal of Pharmacology, 2002, 437(3): 173-178.
21	Ribar B, Kapor A, Mezsaros C, et al. Crystal and molecular structure of chelidonine[J]. ChemInform, 1991, 22(37). doi: 10.1002/chin.199137262. DOI
22	Ambrus A, Chen D, Dai J, et al. Solution structure of the biologically relevant G-quadruplex element in the human c-MYC promoter. Implications for G-quadruplex stabilization[J]. Biochemistry, 2005, 44(6): 2048-2058.
23	Frisch M J. Gaussian 09: Revision A.02[CP]. Wallingford, CT: Gaussian, Inc., 2016.
24	Ivani I, Dans P D, Noy A, et al. PARMBSC1: a refined force-field for DNA simulations[J]. Nature Methods, 2016, 13(1): 55-58.
25	Wang J, Wolf R M, Caldwell J W, et al. Development and testing of a general amber force field[J]. Journal of Computational Chemistry, 2004, 25(9): 1157-1174.
26	Pronk S, Pall S, Schulz R, et al. Gromacs 4.5[J]. Bioinformatics, 2013, 29(7): 845-854.
27	Nose S. A unified formulation of the constant temperature molecular dynamics methods[J]. Journal of Chemical Physics, 1984, 81(1): 511-519.
28	Hoover W G. Canonical dynamics: equilibrium phase-space distributions[J]. Physical Review A, 1985, 31(3): 1695-1697.
29	Parrinello M, Rahman A. Polymorphic transitions in single crystals: a new molecular dynamics method[J]. Journal of Applied Physics, 1981, 52(12): 7182-7190.
30	Hirschfelder J O, Curtiss C F, Bird R B, et al. Molecular Theory of Gases and Liquids[M]. New York: Wiley, 1954.
31	Darden T, York D M, Pedersen L G, et al. Particle mesh Ewald: an N·log(N) method for Ewald sums in large systems[J]. Journal of Chemical Physics, 1993, 98(12): 10089-10092.
32	Kakali B, Gopinatha S K. Interaction of berberine, palmatine, coralyne, and sanguinarine to quadruplex DNA: a comparative spectroscopic and calorimetric study[J]. Biochimica et Biophysica Acta, 2011, 1810: 485-496.

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