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

doi:10.7503/cjcu20170237

Abstract

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

CLC Number:

O641

TrendMD:

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^†[J]. Chem. J. Chinese Universities, 2017, 38(11): 2061.

Figures/Tables 10

References 41

[1]	Cicenas J., Kalyan K., Sorokinas A., Jatulyte A., Valiunas D., Kaupinis A., Valius M., Cancers,2014, 6, 2224-2234
[2]	Asghar U., Witkiewicz A. K., Turner N. C., Knudsen E. S., Chem. J. Chinese Universities,2010, 31, 130-146
[3]	Lim S., Kaldis P., Development,2013, 140, 3079-3087
[4]	Liao Y., Feng Y., Shen J., Hornicek F. J., Duan Z., Cancer and Chem. J. Chinese Universities,2010, 31, 151-163
[5]	Kim M. S., Ji H. K., Jin M. K., Hong S. H., Lee K., Choi H. S., Sang M. W., Chang J. Y., Tai Y. K., Ko S. G. K., Chem. J. Chinese Universities,2010, 31, 3522-3522
[6]	Wang S., Fischer P. M., Chem. J. Chinese Universities,2010, 31, 302-313
[7]	Barrière C., Santamaría D., Cerqueira A., Galán J., Martín A., Ortega S., Malumbres M., Dubus P., Barbacid M., Chem. J. Chinese Universities,2010, 31, 72-81
[8]	Berthet C., Aleem E., Coppola V., Tessarollo L., Kaldis P., Chem. J. Chinese Universities,2010, 31, 1775-1785
[9]	Malumbres M., Sotillo R. O., Santamarí A. D., Galán J., Cerezo A., Ortega S., Dubus P., Barbacid M., Cell,2004, 118, 493-504
[10]	Santamaría D., Barrière C., Cerqueira A., Hunt S., Tardy C., Newton K., Cáceres J. F., Dubus P., Malumbres M., Barbacid M., Nature,2007, 448, 811-815
[11]	Shao H., Shi S., Huang S., Hole A., Abbas A. Y., Baumli S., Liu X., Lam F., Foley D., Fischer P. M., Chem. J. Chinese Universities,2010, 31, 640-659
[12]	Sansó M., Levin R. S., Lipp J. J., Wang V. Y., Greifenberg A. K., Quezada E. M., Ali A., Ghosh A., Larochelle S., Rana T. M., Chem. J. Chinese Universities,2010, 31, 117-129
[13]	Huang C. H., Lujambio A., Zuber J., Tschaharganeh D. F., Doran M. G., Evans M. J., Kitzing T., Zhu N., De S. E., Sawyers C. L., Genes Dev., 2014, 28, 1800-1813
[14]	Walsby E., Pratt G., Shao H., Abbas A. Y., Fischer P. M., Bradshaw T. D., Brennan P., Fegan C., Wang S., Pepper C., Oncotarget,2014, 5, 375-382
[15]	Mariaule G., Belmont P., Molecules,2014, 19, 14366-14382
[16]	Manohar S. M., Rathos M. J., Sonawane V., Rao S. V., Joshi K. S., Chem. J. Chinese Universities,2010, 31, 821-833
[17]	Heathcote D. A., Patel H., Kroll S. H., Hazel P., Periyasamy M., Alikian M., Kanneganti S. K., Jogalekar A. S., Scheiper B., Barbazanges M., Chem. J. Chinese Universities,2010, 31, 8508-8522
[18]	Conroy A., Stockett D. E., Walker D., Arkin M. R., Hoch U., Fox J. A., Hawtin R. E., Cancer Chemotherapy and Pharmacolog,2009, 64, 723-732
[19]	Wu Y., Chen C., Sun X., Shi X., Jin B., Ding K., Yeung S.C., Pan J., Clin. Cancer Res., 2012, 18, 1966-1978
[20]	Bettayeb K., Tirado O. M., Marionneaulambot S., Ferandin Y., Lozach O., Morris J. C., Mateolozano S., Drueckes P., Schächtele C., Kubbutat M. H., Chem. J. Chinese Universities,2010, 31, 8325-8334
[21]	Albert T. K., Rigault C., Eickhoff J., Baumgart K., Antrecht C., Klebl B., Mittler G., Meisterernst M., Chem. J. Chinese Universities,2010, 31, 55-68
[22]	Sawant R. R., Jhaveri A. M., Koshkaryev A., Lin Z., Qureshi F., Torchilin V. P., Chem. J. Chinese Universities,2010, 31, 375-388
[23]	Sonawane Y.A., Taylor M. A., Napoleon J. V., Rana S., Contreras J. I.,Journal of Medicinal Chemistry, 2016, 59-67
[24]	Kryštof V., Baumli S., Fürst R., Chem. J. Chinese Universities,2010, 31, 2883-2890
[25]	Lu H., Xue Y., Xue Y., Yu G. K., Arias C., Lin J., Fong S., Faure M., Weisburd B., Ji X., Chem. J. Chinese Universities,2010, 31
[26]	Wu S. Y., Mcnae I., Kontopidis G., Mcclue S. J., Mcinnes C., Stewart K. J., Wang S., Zheleva D. I., Marriage H., Lane D. P., Struct., 2003, 11, 399-410
[27]	Wang S., Meades C., Wood G., Osnowski A., Anderson S., Yuill R., Thomas M., Mezna M., Jackson W., Midgley C., Chem. J. Chinese Universities,2010, 31, 1662-1670
[28]	Wang S., Griffiths G., Midgley C. A., Barnett A. L., Cooper M., Grabarek J., Ingram L., Jackson W., Kontopidis G., Mcclue S. J., Chem. J. Chinese Universities,2010, 31, 1111-1121
[29]	Lukasik P. M., Elabar S., Lam F., Shao H., Liu X., Abbas A. Y., Wang S., European Journal of Medicinal Chemistry,2012, 57, 311-322
[30]	Shao H., Shi S., Foley D. W., Lam F., Abbas A. Y., Liu X., Huang S., Jiang X., Baharin N., Fischer P. M., European Journal of Medicinal Chemistry,2013, 70, 447-455
[31]	Németh G., Varga Z., Greff Z., Bencze G., Sipos A., Szántaikis C., Baska F., Gyuris A., Kelemenics K., Szathmáry Z., Chem. J. Chinese Universities,2010, 31, 342-358
[32]	Nemeth G., Greff Z., Sipos A., Varga Z., Szekely R., Sebestyen M., Jaszay Z., Beni S., Nemes Z., Pirat J. L., Volle J. N., Virieux D., Gyuris A., Kelemenics K., Ay E., Minarovits J., Szathmary S., Keri G., Orfi L., J. Med. Chem., 2014, 57, 3939-3965
[33]	Zhang Q. Q., Yao Q. Z., Zhang S. P., Bi L. M., Zhou Z. G., Zhang J., Acta Phys. Chim. Sin., 2014, 30, 371-381
	(张青青, 姚其正, 张生平, 毕乐明, 周之光, 张骥. 物理化学学报, 2014, 30, 371-381)
[34]	Liu B. G., Liu J. W., Li J. Q., Geng S., Mo H. Z., Liang G. Z., Chem. J. Chinese Universities., 2017, 38(1), 41-46
	(刘本国, 刘江伟, 李嘉琪, 耿升, 莫海珍, 梁桂兆. 高等学校化学学报, 2017, 38(1), 41-46)
[35]	Chen W. Y., Wang S. S., Li D. L., Peng W., Zhao J. F., Duan H. X., Chem. J. Chinese Universities., 2013, 34(12), 2798-2805
	陈文雅, 王珊珊, 李冬玲, 彭炜, 赵静馥, 段红霞. 高等学校化学学报, 2013, 34(12), 2798-2805
[36]	Chen Y., Cai X., Jiang L., Li Y., Ecotoxicology and Chem. J. Chinese Universities,2010, 31, 202-215
[37]	Li B., Zhou R., He G., Guo L., Huang W., Chem. J. Chinese Universities,2010, 31, 1396-1403
	(李博, 周锐, 何谷, 郭丽, 黄维. 化学学报, 2013, 71, 1396-1403)
[38]	Czudnochowski N., Bösken C. A., Geyer M., Chem. J. Chinese Universities,2010, 31, 842-854
[39]	Hole A. J., Baumli S., Shao H., Shi S., Huang S., Pepper C., Fischer P. M., Wang S., Endicott J. A., Noble M. E., Chem. J. Chinese Universities,2010, 31, 660-670
[40]	Baumli S., Hole A. J., Noble M. E., Endicott J. A., Chem. J. Chinese Universities,2010, 31, 811-822
[41]	Li X., Ye L., Wang X., Shi W., Qian X., Zhu Y., Yu H., Chem. J. Chinese Universities,2010, 31, 357-367

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