Citation: ZHANG Qing-Qing, YAO Qi-Zheng, ZHANG Sheng-Ping, BI Le-Ming, ZHOU Zhi-Guang, ZHANG Ji. Homology Modeling, Molecular Docking, and 3D-QSAR of Indirubin Analogues as CDK1 Inhibitors[J]. Acta Physico-Chimica Sinica, 2014, 30(2): 371-381. doi: 10.3866/PKU.WHXB201312192
靛玉红类CDK1抑制剂的同源模建、分子对接及3D-QSAR研究
细胞周期蛋白依赖性激酶1的异常表达会导致G2期的停滞及多种肿瘤的发生，故CDK1近年来已成为一个理想的治疗靶点. 本文以细胞分裂调控蛋白2的同源体为模板，同源模建了CDK1的结构，并与靛玉红类小分子抑制剂进行分子对接. 分别运用三种叠合方法进行分子叠合，并在此基础上采用Sybyl 7.1中的比较分子场分析(CoMFA)模块及Discovery Studio 3.0中的三维定量构效关系(3D-QSAR)模块(以下简称为DS)分别建立了3D-QSAR模型. 其中，将分子对接叠合与公共骨架叠合联合运用的叠合方法所得3D-QSAR模型的评价参数是最佳的(CoMFA：q2=0.681，r2=0.909，rpred.2=0.836； DS：q2=0.579，r2=0.971，rpred.2=0.795，其中q2为交叉验证系数，r2为非交叉验证系数). 本文的研究结果在对靛玉红类小分子进行结构修饰设计出新的CDK1抑制剂方面，可提供重要的理论基础.
-
关键词:
-
细胞周期蛋白依赖性激酶1
- / 靛玉红
- / 3D-QSAR
- / 比较分子场分析
- / 同源模建
English
Homology Modeling, Molecular Docking, and 3D-QSAR of Indirubin Analogues as CDK1 Inhibitors
The abnormal expression of cyclin-dependent kinase 1 (CDK1) leads to stagnation of the G2 phase and a variety of tumors. Therefore, CDK1 has been reported recently as an ideal cell cycle target for cancer drug discovery. In this paper, we use the cell division control protein 2 homolog as a template to homologically model the protein of CDK1 that is subsequently docked with the inhibitors of indirubin analogues. Three molecular alignment methods were used, and the corresponding three- dimensional quantitative structure-activity relationship (3D-QSAR) models were built using the comparative molecular field analysis (CoMFA) protocol in Sybyl 7.1 and the 3D-QSAR protocol (abbreviated for DS) in Discovery Studio 3.0. It was found that the molecular alignment method combining molecular docking with public template is most suitable for building the 3D-QSARmodels, and shows the best calculated results (CoMFA: q2=0.681, r2=0.909, and rpred.2=0.836; DS: q2= 0.579, r2=0.971, and rpred.2=0.795, where q2 denotes the cross-validated correlation coefficient and r2 denotes the non- cross- validated correlation coefficient). This paper may provide significant theoretical foundation for designing novel CDK1 inhibitors by carrying out structural modifications of indirubin analogues.
-
Key words:
-
Cyclin-dependent kinase 1
- / Indirubin
- / 3D-QSAR
- / CoMFA
- / Homology modeling
-
-
[1]
(1) Lees, E. Curr. Opin. Cell Biol. 1995, 7 (6), 773. doi: 10.1016/0955-0674(95)80060-3
(1) Lees, E. Curr. Opin. Cell Biol. 1995, 7 (6), 773. doi: 10.1016/0955-0674(95)80060-3
-
[2]
(2) Zhang, L.; Zhu, H.;Wang, Q.; Fang, H.; Xu,W.; Li, M. J. Mol. Model. 2011, 17 (2), 219. doi: 10.1007/s00894-010-0710-z(2) Zhang, L.; Zhu, H.;Wang, Q.; Fang, H.; Xu,W.; Li, M. J. Mol. Model. 2011, 17 (2), 219. doi: 10.1007/s00894-010-0710-z
-
[3]
(3) Quereda, V.; Malumbres, M. J. Mol. Endocrinol. 2009, 42 (2),75.(3) Quereda, V.; Malumbres, M. J. Mol. Endocrinol. 2009, 42 (2),75.
-
[4]
(4) Santamaria, D.; Barriere, C.; Cerqueira, A.; Hunt, S.; Tardy, C.;Newton, K.; Caceres, J. F.; Dubus, P.; Malumbres, M.; Barbacid,M. Nature 2007, 448 (7155), 811. doi: 10.1038/nature06046(4) Santamaria, D.; Barriere, C.; Cerqueira, A.; Hunt, S.; Tardy, C.;Newton, K.; Caceres, J. F.; Dubus, P.; Malumbres, M.; Barbacid,M. Nature 2007, 448 (7155), 811. doi: 10.1038/nature06046
-
[5]
(5) Wang, Q.; Su, L.; Niu, N.; Zhang, L.; Xu,W.; Fang, H. Curr. Med. Chem. 2011, 18 (13), 2025. doi: 10.2174/092986711795590110(5) Wang, Q.; Su, L.; Niu, N.; Zhang, L.; Xu,W.; Fang, H. Curr. Med. Chem. 2011, 18 (13), 2025. doi: 10.2174/092986711795590110
-
[6]
(6) Singh, S. K.; Dessalew, N.; Bharatam, P. V. Med. Chem. 2007, 3 (1), 75. doi: 10.2174/157340607779317517(6) Singh, S. K.; Dessalew, N.; Bharatam, P. V. Med. Chem. 2007, 3 (1), 75. doi: 10.2174/157340607779317517
-
[7]
(7) McGrath, C. F.; Pattabiraman, N.; Kellogg, G. E.; Lemcke, T.;Kunick, C.; Sausville, E. A.; Zaharevitz, D.W.; Gussio, R.J. Biomol. Struct. Dyn. 2005, 22 (5), 493. doi: 10.1080/07391102.2005.10531227(7) McGrath, C. F.; Pattabiraman, N.; Kellogg, G. E.; Lemcke, T.;Kunick, C.; Sausville, E. A.; Zaharevitz, D.W.; Gussio, R.J. Biomol. Struct. Dyn. 2005, 22 (5), 493. doi: 10.1080/07391102.2005.10531227
-
[8]
(8) Gussio, R.; Zaharevitz, D.W.; McGrath, C. F.; Pattabiraman,N.; Kellogg, G. E.; Schultz, C.; Link, A.; Kunick, C.; Leost, M.;Meijer, L.; Sausville, E. A. Anticancer Drug Des. 2000, 15 (1),53.(8) Gussio, R.; Zaharevitz, D.W.; McGrath, C. F.; Pattabiraman,N.; Kellogg, G. E.; Schultz, C.; Link, A.; Kunick, C.; Leost, M.;Meijer, L.; Sausville, E. A. Anticancer Drug Des. 2000, 15 (1),53.
-
[9]
(9) Li,W. Y.; Zhang, L.; Li, F. L.;Wang, Z. H.; Yao, Q. Z. World Notes Antibiot. 2009, 30 (3), 113. [李文赟, 张磊, 李福龙,王朝晖, 姚其正. 国外医药抗生分册, 2009, 30 (3), 113.](9) Li,W. Y.; Zhang, L.; Li, F. L.;Wang, Z. H.; Yao, Q. Z. World Notes Antibiot. 2009, 30 (3), 113. [李文赟, 张磊, 李福龙,王朝晖, 姚其正. 国外医药抗生分册, 2009, 30 (3), 113.]
-
[10]
(10) Beauchard, A.; Ferandin, Y.; Frere, S.; Lozach, O.; Blairvacq,M.; Meijer, L.; Thiery, V.; Besson, T. Bioorganic & Medicinal Chemistry 2006, 14 (18), 6434. doi: 10.1016/j.bmc.2006.05.036(10) Beauchard, A.; Ferandin, Y.; Frere, S.; Lozach, O.; Blairvacq,M.; Meijer, L.; Thiery, V.; Besson, T. Bioorganic & Medicinal Chemistry 2006, 14 (18), 6434. doi: 10.1016/j.bmc.2006.05.036
-
[11]
(11) Ferandin, Y.; Bettayeb, K.; Kritsanida, M.; Lozach, O.;Polychronopoulos, P.; Magiatis, P.; Skaltsounis, A. L.; Meijer,L. J. Med. Chem. 2006, 49 (15), 4638. doi: 10.1021/jm060314i(11) Ferandin, Y.; Bettayeb, K.; Kritsanida, M.; Lozach, O.;Polychronopoulos, P.; Magiatis, P.; Skaltsounis, A. L.; Meijer,L. J. Med. Chem. 2006, 49 (15), 4638. doi: 10.1021/jm060314i
-
[12]
(12) Leclerc, S.; Garnier, M.; Hoessel, R.; Marko, D.; Bibb, J. A.;Snyder, G. L.; Greengard, P.; Biernat, J.;Wu, Y. Z.; Mandelkow,E. M.; Eisenbrand, G.; Meijer, L. J. Biol. Chem. 2001, 276 (1),251.(12) Leclerc, S.; Garnier, M.; Hoessel, R.; Marko, D.; Bibb, J. A.;Snyder, G. L.; Greengard, P.; Biernat, J.;Wu, Y. Z.; Mandelkow,E. M.; Eisenbrand, G.; Meijer, L. J. Biol. Chem. 2001, 276 (1),251.
-
[13]
(13) Meijer, L.; Skaltsounis, A. L.; Magiatis, P.; Polychronopoulos,P.; Knockaert, M.; Leost, M.; Ryan, X. P.; Vonica, C. A.;Brivanlou, A.; Dajani, R.; Crovace, C.; Tarricone, C.;Musacchio, A.; Roe, S. M.; Pearl, L.; Greengard, P. Chem. Biol.2003, 10 (12), 1255. doi: 10.1016/j.chembiol.2003.11.010(13) Meijer, L.; Skaltsounis, A. L.; Magiatis, P.; Polychronopoulos,P.; Knockaert, M.; Leost, M.; Ryan, X. P.; Vonica, C. A.;Brivanlou, A.; Dajani, R.; Crovace, C.; Tarricone, C.;Musacchio, A.; Roe, S. M.; Pearl, L.; Greengard, P. Chem. Biol.2003, 10 (12), 1255. doi: 10.1016/j.chembiol.2003.11.010
-
[14]
(14) Hyperchem, Release 7.0 forWindows; Hypercube, Inc.:Gainesville, 2002.(14) Hyperchem, Release 7.0 forWindows; Hypercube, Inc.:Gainesville, 2002.
-
[15]
(15) Robbins, T. J.;Wang, Y.; Yao, Q. Z.;Wang, Z. H.; Cheng, J.; Li,Y. S. J. Mol. Struct. 2013, 1048, 51. doi: 10.1016/j.molstruc.2013.05.012(15) Robbins, T. J.;Wang, Y.; Yao, Q. Z.;Wang, Z. H.; Cheng, J.; Li,Y. S. J. Mol. Struct. 2013, 1048, 51. doi: 10.1016/j.molstruc.2013.05.012
-
[16]
(16) Tian, F. A.; Li, C. M.; ng, K. C.; Zhou, Z. H.; Mao, Z. H.;Guo, Y. H. Chin. J. Med. Chem. 1994, 4 (12), 101. [田发安, 李春敏, 龚考才, 周宗华, 毛治华, 郭韵洪. 中国药物化学杂志,1994, 4 (12), 101.](16) Tian, F. A.; Li, C. M.; ng, K. C.; Zhou, Z. H.; Mao, Z. H.;Guo, Y. H. Chin. J. Med. Chem. 1994, 4 (12), 101. [田发安, 李春敏, 龚考才, 周宗华, 毛治华, 郭韵洪. 中国药物化学杂志,1994, 4 (12), 101.]
-
[17]
(17) Discovery Studio 3.0; Accelrys Inc.: San Die , CA.(17) Discovery Studio 3.0; Accelrys Inc.: San Die , CA.
-
[18]
(18) Honma, T.; Hayashi, K.; Aoyama, T.; Hashimoto, N.; Machida,T.; Fukasawa, K.; Iwama, T.; Ikeura, C.; Ikuta, M.; Suzuki-Takahashi, I.; Iwasawa, Y.; Hayama, T.; Nishimura, S.;Morishima, H. J. Med. Chem. 2001, 44 (26), 4615. doi: 10.1021/jm0103256(18) Honma, T.; Hayashi, K.; Aoyama, T.; Hashimoto, N.; Machida,T.; Fukasawa, K.; Iwama, T.; Ikeura, C.; Ikuta, M.; Suzuki-Takahashi, I.; Iwasawa, Y.; Hayama, T.; Nishimura, S.;Morishima, H. J. Med. Chem. 2001, 44 (26), 4615. doi: 10.1021/jm0103256
-
[19]
(19) Ikuta, M.; Kamata, K.; Fukasawa, K.; Honma, T.; Machida, T.;Hirai, H.; Suzuki-Takahashi, I.; Hayama, T.; Nishimura, S.J. Biol. Chem. 2001, 276 (29), 27548. doi: 10.1074/jbc.M102060200(19) Ikuta, M.; Kamata, K.; Fukasawa, K.; Honma, T.; Machida, T.;Hirai, H.; Suzuki-Takahashi, I.; Hayama, T.; Nishimura, S.J. Biol. Chem. 2001, 276 (29), 27548. doi: 10.1074/jbc.M102060200
-
[20]
(20) Zhang, N.; Jiang, Y. J.; Zou, J.W.; Zeng, M.; Hu, G. X.; Yu, Q.S. Acta. Chim. Sin. 2005, 63 (9), 809. [张娜, 蒋勇军, 邹建卫, 曾敏, 胡桂香, 俞庆森. 化学学报, 2005, 63 (9), 809.](20) Zhang, N.; Jiang, Y. J.; Zou, J.W.; Zeng, M.; Hu, G. X.; Yu, Q.S. Acta. Chim. Sin. 2005, 63 (9), 809. [张娜, 蒋勇军, 邹建卫, 曾敏, 胡桂香, 俞庆森. 化学学报, 2005, 63 (9), 809.]
-
[21]
(21) Davies, T. G.; Tunnah, P.; Meijer, L.; Marko, D.; Eisenbrand,G.; Endicott, J. A.; Noble, M. E. M. Structure 2001, 9 (5),389. doi: 10.1016/S0969-2126(01)00598-6(21) Davies, T. G.; Tunnah, P.; Meijer, L.; Marko, D.; Eisenbrand,G.; Endicott, J. A.; Noble, M. E. M. Structure 2001, 9 (5),389. doi: 10.1016/S0969-2126(01)00598-6
-
[22]
(22) Polychronopoulos, P.; Magiatis, P.; Skaltsounis, A. L.;Myrianthopoulos, V.; Mikros, E.; Tarricone, A.; Musacchio, A.;Roe, S. M.; Pearl, L.; Leost, M.; Greengard, P.; Meijer, L.J. Med. Chem. 2004, 47 (4), 935. doi: 10.1021/jm031016d(22) Polychronopoulos, P.; Magiatis, P.; Skaltsounis, A. L.;Myrianthopoulos, V.; Mikros, E.; Tarricone, A.; Musacchio, A.;Roe, S. M.; Pearl, L.; Leost, M.; Greengard, P.; Meijer, L.J. Med. Chem. 2004, 47 (4), 935. doi: 10.1021/jm031016d
-
[23]
(23) SYBYL 7.1; Tripos Inc.: St. Louis, Missouri, 63144, U.S.A.
(23) SYBYL 7.1; Tripos Inc.: St. Louis, Missouri, 63144, U.S.A.
-
[1]
-
扫一扫看文章
计量
- PDF下载量: 768
- 文章访问数: 1677
- HTML全文浏览量: 141
下载:
