含磷嘧啶类CDK9抑制剂的分子对接、3D-QSAR和分子动力学模拟

doi:10.7503/cjcu20170237

高等学校化学学报 ›› 2017, Vol. 38 ›› Issue (11): 2061.doi: 10.7503/cjcu20170237

含磷嘧啶类CDK9抑制剂的分子对接、3D-QSAR和分子动力学模拟

唐光辉¹, 张娅¹, 张玉萍¹, 周朋朋¹, 林治华¹, 王远强^1,²()

1. 重庆理工大学药学与生物工程学院, 重庆 400054
2. 药物化学与分子药理学重庆市重点实验室, 重庆 400054

收稿日期:2017-04-17 出版日期:2017-11-10 发布日期:2017-10-30
作者简介:联系人简介: 王远强, 男, 博士, 副教授, 主要从事生物信息学和药物化学研究. E-mail: wangyqnn@cqut.edu.cn
基金资助:
国家自然科学基金(批准号: 31400667)、重庆市教委科学技术研究项目(批准号: KJ1400932, KJ1500902, KJ1600908)、重庆市基础研究与前沿技术研究项目(批准号: csc2014jcyjA10044, cstc2013jcyjA10019)和重庆高校创新团队建设计划项目(批准号: CXTDX201601031)资助

Molecular Docking, QSAR and Molecular Dynamics Simulation on Phosphorus Containing Pyrimidines as CDK9 Inhibitors^†

TANG Guanghui¹, ZHANG Ya¹, ZHANG Yuping¹, ZHOU Pengpeng¹, LIN Zhihua¹, WANG Yuanqiang^1,^2,^*()

1. College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
2. Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing 400054, China

Received:2017-04-17 Online:2017-11-10 Published:2017-10-30
Contact: WANG Yuanqiang E-mail:wangyqnn@cqut.edu.cn
Supported by:
† Supported by the National Natural Science Foundation of China(No.31400667), the Scientific and Technological Research Program of Chongqing Municipal Education Commission, China(Nos.KJ1400932, KJ1500902, KJ1600908), the Chongqing Research Program of Basic Research and Frontier Technology, China(Nos.csc2014jcyjA10044, cstc2013jcyjA10019) and the Program for Innovation Team Building at Institutions of Higher Education in Chongqing, China(No.CXTDX201601031)

摘要/Abstract

摘要：

选取64个具有潜力的含磷嘧啶类细胞周期依赖性蛋白激酶(CDK9)小分子抑制剂, 采用分子对接方法研究了该类小分子与CDK9的结合作用, 结果表明, 分子构象、氢键形成、疏水性和氨基酸残基Cys106在此类抑制剂与CDK9的结合过程中具有重要作用. 在配体叠合的基础上, 运用比较分子力场分析(CoMFA)、比较分子相似性指数分析(CoMSIA)和Topomer CoMFA(T-COMFA)研究了分子结构与抑制活性的关系, 发现由训练集立体场、静电场和疏水场组合的CoMSIA模型为最优模型, 其内部交叉验证相关系数(Q²=0.557)、非交叉验证相关系数(R²=0.959)和外部预测相关系数(r²=0.863)具有统计学意义, 该模型的三维等值线图直观显示了化合物的活性与其三维结构的关系. 根据这些结果设计了10个具有新结构的含磷嘧啶类化合物, 分子对接和分子动力学模拟结果表明, 新化合物和CDK9的结合模式与原化合物64相同, 自由能分析从理论上证明了新化合物64d的CDK9抑制活性优于化合物64, 并且显示含磷基团与残基Asp109的静电场能在化合物与CDK9作用过程中有重要作用.

关键词: 含磷嘧啶类细胞周期依赖性蛋白激酶抑制剂, 分子对接, 比较分子力场分析, 比较分子相似性指数分析, Topomer CoMFA, 分子动力学

Abstract:

The interaction modes between phosphorus containing pyrimidine cyclin dependent kinase 9(CDK9) inhibitors and the protein were studied using the combination of molecular docking and three-dimensional quantitative structure-activity relationships(3D-QSAR). The interaction mode obtained by molecular docking revealed that the molecule conformation, hydrophobic interaction and H-bond, as well as Cys106 played an important role in the binding of phosphorus containing pyrimidines and CDK9. Based on the result of molecular docking, 3D-QSAR models were established by comparative molecular field analysis(CoMFA), comparative molecular similarity indices analysis(CoMSIA) and Topomer CoMFA techniques. With the best CoMSIA-SEH model, the cross-validated value(Q²) was 0.557, the non-cross-validated value(R²) was 0.959. The predictive power of the CoMSIA-SEH model was determined from external test sets that were excluded during model development(r²=0.863). Ten new compounds were obtained based on the above modeling, and the results of molecular docking and molecular dynamics simulation suggested they could act as potential CDK9 inhibitors, especially compound 64d with more potent inhibitory activity proved by molecular dynamics simulation and binding free energy analysis. It was expected that these results could help establish the binding mechanism between phosphorus containing pyrimidines and CDK9, and provide a valuable reference for future anti-CDK9 drug design.

Key words: Cyclin dependent kinase(CDK9) inhibitor, Surflex-dock, Comparative molecular field analysis(CoMFA), Comparative molecular similarity indices analysis(CoMSIA), Topomer CoMFA, Molecular dynamics

中图分类号:

O641

TrendMD:

唐光辉, 张娅, 张玉萍, 周朋朋, 林治华, 王远强. 含磷嘧啶类CDK9抑制剂的分子对接、3D-QSAR和分子动力学模拟. 高等学校化学学报, 2017, 38(11): 2061.

TANG Guanghui, ZHANG Ya, ZHANG Yuping, ZHOU Pengpeng, LIN Zhihua, WANG Yuanqiang. Molecular Docking, QSAR and Molecular Dynamics Simulation on Phosphorus Containing Pyrimidines as CDK9 Inhibitors^†. Chem. J. Chinese Universities, 2017, 38(11): 2061.

图/表 10

参考文献 41

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Method	Parameter
Method	n	Q²	R²	SEE	F	r²	SDEP
CoMFA	4	0.162	0.876	0.196	81.257	0.376	0.357
CoMSIA-EH	7	0.564	0.950	0.129	115.848	0.765	0.211
CoMSIA-SEH	7	0.557	0.959	0.116	145.518	0.863	0.097
T-CoMFA	11	0.719	0.964			0.629	0.344

Method	Parameter
Method	n	Q²	R²	SEE	F	r²	SDEP
CoMFA	4	0.162	0.876	0.196	81.257	0.376	0.357
CoMSIA-EH	7	0.564	0.950	0.129	115.848	0.765	0.211
CoMSIA-SEH	7	0.557	0.959	0.116	145.518	0.863	0.097
T-CoMFA	11	0.719	0.964			0.629	0.344

Compound	R₅	R₆	R₇	Z₁	Z₂	Calculated pIC₅₀
Compound	R₅	R₆	R₇	Z₁	Z₂	CoMSIA-EH	CoMSIA-SEH	T-CoMFA
64	H	H	H	H	H	3.830	3.873	3.880
64a	H	Et	H	OCH₃	H	3.485	3.457	3.770
64b	H	H	H	H	Et	3.378	3.349	3.880
64c	H	H	H	BnO	H	3.680	3.568	3.820
64d	H	H	SOOH	H	H	3.916	3.947	3.920
64e	H	H	SOOCH₃	H	H	3.952	3.962	3.882
64f	H	Et	SOOH	H	H	3.830	3.782	3.878
64g	H	Et	SO₃CH₃	H	H	3.988	4.012	3.860
64h	H	Et	SOOCH₃	H	H	3.980	3.989	3.830
64i	F	Et	SO₃CH₃	H	H	3.826	3.875	3.650
64j	H	H	4-piperidyl	H	H	3.825	3.869	3.890

Compound	R₅	R₆	R₇	Z₁	Z₂	Calculated pIC₅₀
Compound	R₅	R₆	R₇	Z₁	Z₂	CoMSIA-EH	CoMSIA-SEH	T-CoMFA
64	H	H	H	H	H	3.830	3.873	3.880
64a	H	Et	H	OCH₃	H	3.485	3.457	3.770
64b	H	H	H	H	Et	3.378	3.349	3.880
64c	H	H	H	BnO	H	3.680	3.568	3.820
64d	H	H	SOOH	H	H	3.916	3.947	3.920
64e	H	H	SOOCH₃	H	H	3.952	3.962	3.882
64f	H	Et	SOOH	H	H	3.830	3.782	3.878
64g	H	Et	SO₃CH₃	H	H	3.988	4.012	3.860
64h	H	Et	SOOCH₃	H	H	3.980	3.989	3.830
64i	F	Et	SO₃CH₃	H	H	3.826	3.875	3.650
64j	H	H	4-piperidyl	H	H	3.825	3.869	3.890

Method	Compound	ΔG_vdW/ (kJ·mol^-1)	ΔG_ele/ (kJ·mol^-1)	ΔG_epb/ (kJ·mol^-1)	ΔG_enp/ (kJ·mol^-1)	ΔG_edi/ (kJ·mol^-1)	ΔG_pred/ (kJ·mol^-1)
PBSA	64	-235.92	-169.07	294.49	-156.05	282.81	16.16
	64d	-247.77	-226.50	342.00	-179.54	313.70	1.88
Method	Compound	ΔG_vdW/ (kJ·mol^-1)	ΔG_ele/ (kJ·mol^-1)	ΔG_ele,sol/ (kJ·mol^-1)	ΔG_nonpol,sol/ (kJ·mol^-1)	ΔG_pred/ (kJ·mol^-1)
GBSA	64	-235.92	-169.07	237.72	-28.30	-195.61
	64d	-247.77	-226.50	277.82	-33.74	-23.23

含磷嘧啶类CDK9抑制剂的分子对接、3D-QSAR和分子动力学模拟

Molecular Docking, QSAR and Molecular Dynamics Simulation on Phosphorus Containing Pyrimidines as CDK9 Inhibitors^†

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含磷嘧啶类CDK9抑制剂的分子对接、3D-QSAR和分子动力学模拟

Molecular Docking, QSAR and Molecular Dynamics Simulation on Phosphorus Containing Pyrimidines as CDK9 Inhibitors†

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Molecular Docking, QSAR and Molecular Dynamics Simulation on Phosphorus Containing Pyrimidines as CDK9 Inhibitors^†