五元杂环并嘧啶类胸苷酸合成酶抑制剂的构效关系和分子对接

引用本文: 康从民, 赵绪浩, 王新宇, 程家高, 吕英涛. 五元杂环并嘧啶类胸苷酸合成酶抑制剂的构效关系和分子对接[J]. 物理化学学报, 2013, 29(02): 431-438. doi: 10.3866/PKU.WHXB201211151 shu

Citation: KANG Cong-Min, ZHAO Xu-Hao, WANG Xin-Yu, CHENG Jia-Gao, LÜ Ying-Tao. QSAR and Molecular Docking on Five-Membered Heterocyclopyrimidines as Thymidylate Synthase Inhibitors[J]. Acta Physico-Chimica Sinica, 2013, 29(02): 431-438. doi: 10.3866/PKU.WHXB201211151 shu

五元杂环并嘧啶类胸苷酸合成酶抑制剂的构效关系和分子对接

基金项目:
国家自然科学基金(21072111, 21172070, 21272131) (21072111, 21172070, 21272131)

山东省自然科学基金(ZR2011BM015)资助项目 (ZR2011BM015)

摘要:

用比较分子场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)研究了38个五元杂环并嘧啶衍生物类胸苷酸合成酶抑制剂的三维定量构效关系(3D-QSAR), 建立了相关预测模型. CoMFA和CoMSIA模型的交互验证相关系数q²分别为0.662和0.672、非交互验证相关系数R²分别为0.921和0.884、外部交互验证相关系数Q_ext²分别为0.85和0.81. 分子对接得到的结合模式与三维定量构效关系得到的结果一致. 结果表明这两种模型都具有良好的预测能力, 可应用于指导化合物的设计和结构修饰, 为进一步设计新型胸苷酸合成酶抑制剂提供了理论依据.

关键词:

English

QSAR and Molecular Docking on Five-Membered Heterocyclopyrimidines as Thymidylate Synthase Inhibitors

1.
1 College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, Shandong Province, P. R. China;
2 Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China
Received Date: 27 August 2012
Available Online: 14 January 2013
Fund Project:
国家自然科学基金(21072111, 21172070, 21272131)

山东省自然科学基金(ZR2011BM015)资助项目

Abstract:

The three-dimensional quantitative structure-activity relationships (3D-QSAR) were established for 38 five-membered heterocyclopyrimidine thymidylate synthase inhibitors by using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) techniques. With the CoMFA model, the cross-validated value (q²) was 0.662, the non-cross-validated value (R²) was 0.921, and the external cross-validated value (Q_ext²) was 0.85. And with the CoMSIA model, the corresponding q², R², and Q_ext² values were 0.672, 0.884, and 0.81, respectively. The mode of action obtained by molecular docking was in agreement with the 3D-QSAR results. The results revealed that both models have od predictive capability to guide the design and structural modification of homologic compounds. Furthermore, these results also establish a base level for further research and development of new thymidylate synthase inhibitors.

Key words:

1. [1]
  
  (1) Doan, L. T.; Martucci,W. E.; Var , M. A.; Atreya, C. E.;Anderson, K. S. Biochemistry 2007, 46, 8379. doi: 10.1021/bi700531r
  (1) Doan, L. T.; Martucci,W. E.; Var , M. A.; Atreya, C. E.;Anderson, K. S. Biochemistry 2007, 46, 8379. doi: 10.1021/bi700531r
2. [2]
  (2) Hardy, L.W.; Finer-Moore, J. S.; Montfort,W. R.; Jones, M. O.;Santi, D. V.; Stroud, R. M. Science 1987, 235, 448. doi: 10.1126/science.3099389(2) Hardy, L.W.; Finer-Moore, J. S.; Montfort,W. R.; Jones, M. O.;Santi, D. V.; Stroud, R. M. Science 1987, 235, 448. doi: 10.1126/science.3099389
3. [3]
  (3) Gangjee, A.; Kurup, S.; Namjoshi, O. Curr. Pharm. Des. 2007,13, 609. doi: 10.2174/138161207780162827(3) Gangjee, A.; Kurup, S.; Namjoshi, O. Curr. Pharm. Des. 2007,13, 609. doi: 10.2174/138161207780162827
4. [4]
  (4) Gangjee, A.; Zaware, N.; Raghavan, S.; Ihnat, M.; Shenoy, S.;Kisliuk, R. L. J. Med. Chem. 2010, 53, 1563. doi: 10.1021/jm9011142(4) Gangjee, A.; Zaware, N.; Raghavan, S.; Ihnat, M.; Shenoy, S.;Kisliuk, R. L. J. Med. Chem. 2010, 53, 1563. doi: 10.1021/jm9011142
5. [5]
  (5) Gangjee, A.; Jain, H. D.; Phan, J.; Lin, X.; Song, X. H.;McGuire, J. J.; Kisliuk, R. L. J. Med. Chem. 2006, 49, 1055.doi: 10.1021/jm058276a(5) Gangjee, A.; Jain, H. D.; Phan, J.; Lin, X.; Song, X. H.;McGuire, J. J.; Kisliuk, R. L. J. Med. Chem. 2006, 49, 1055.doi: 10.1021/jm058276a
6. [6]
  (6) Gangjee, A.; Li,W.; Kisliuk, R. L.; Cody, V.; Pace, J.; Piraino,J.; Makin, J. J. Med. Chem. 2009, 52, 4892. doi: 10.1021/jm900490a(6) Gangjee, A.; Li,W.; Kisliuk, R. L.; Cody, V.; Pace, J.; Piraino,J.; Makin, J. J. Med. Chem. 2009, 52, 4892. doi: 10.1021/jm900490a
7. [7]
  (7) Gangjee, A.; Li,W.; Yang, J.; Kisliuk, R. L. J. Med. Chem.2008, 51, 68. doi: 10.1021/jm701052u(7) Gangjee, A.; Li,W.; Yang, J.; Kisliuk, R. L. J. Med. Chem.2008, 51, 68. doi: 10.1021/jm701052u
8. [8]
  (8) Costi, M.; Tondi, D.; Rinaldi, M.; Barlocco, D.; Pecorari, P.;Soragni, F.; Veturelli, A.; Stroud, R. M. Biochim. Biophys. Acta2002, 1587, 206. doi: 10.1016/S0925-4439(02)00083-2(8) Costi, M.; Tondi, D.; Rinaldi, M.; Barlocco, D.; Pecorari, P.;Soragni, F.; Veturelli, A.; Stroud, R. M. Biochim. Biophys. Acta2002, 1587, 206. doi: 10.1016/S0925-4439(02)00083-2
9. [9]
  (9) Zhang, Y.; Chen, Y. D.; You, Q. D.; Zou, L. Y.; Yang, Y. Acta Phys. -Chim. Sin. 2010, 26, 1676. [章媛, 陈亚东, 尤启冬,邹丽云, 杨燕. 物理化学学报, 2010, 26, 1676.] doi: 10.3866/PKU.WHXB20100645(9) Zhang, Y.; Chen, Y. D.; You, Q. D.; Zou, L. Y.; Yang, Y. Acta Phys. -Chim. Sin. 2010, 26, 1676. [章媛, 陈亚东, 尤启冬,邹丽云, 杨燕. 物理化学学报, 2010, 26, 1676.] doi: 10.3866/PKU.WHXB20100645
10. [10]
  (10) Duan, H. X.;Wang, R. G.; Zhang, J. J.; Dong, Y. H.; Liang, X.M.;Wu, J. P.;Wang, D. Q. Acta Phys. -Chim. Sin. 2010, 26,1065. [段红霞, 王瑞刚, 张建军, 董燕红, 梁晓梅, 吴景平,王道全. 物理化学学报, 2010, 26, 1065.] doi: 10.3866/PKU.WHXB20100435(10) Duan, H. X.;Wang, R. G.; Zhang, J. J.; Dong, Y. H.; Liang, X.M.;Wu, J. P.;Wang, D. Q. Acta Phys. -Chim. Sin. 2010, 26,1065. [段红霞, 王瑞刚, 张建军, 董燕红, 梁晓梅, 吴景平,王道全. 物理化学学报, 2010, 26, 1065.] doi: 10.3866/PKU.WHXB20100435
11. [11]
  (11) Kunal, R.; Thomas, L. J. Bioorg. Med. Chem. 2005, 13 (8),2967. doi: 10.1016/j.bmc.2005.02.003(11) Kunal, R.; Thomas, L. J. Bioorg. Med. Chem. 2005, 13 (8),2967. doi: 10.1016/j.bmc.2005.02.003
12. [12]
  (12) Zhu, J.; Zhang,W. N.; Ji, H. T.; Zhou, Y. J.; Zhu, J.; Lü, J. G.Chinese Journal of Medicinal Chemistry 1999, 9 (4), 277.[朱杰, 张万年, 季海涛, 周有骏, 朱驹, 吕加国. 中国药物化学杂志, 1999, 9 (4), 277.](12) Zhu, J.; Zhang,W. N.; Ji, H. T.; Zhou, Y. J.; Zhu, J.; Lü, J. G.Chinese Journal of Medicinal Chemistry 1999, 9 (4), 277.[朱杰, 张万年, 季海涛, 周有骏, 朱驹, 吕加国. 中国药物化学杂志, 1999, 9 (4), 277.]
13. [13]
  (13) Ding, J. J.; Ding, X. Q.; Zhao, L. F.; Chen, J. S. Acta Phys. -Chim. Sin. 2003, 19, 1108. [丁俊杰, 丁晓琴, 赵立峰,陈冀胜. 物理化学学报, 2003, 19, 1108.] doi: 10.3866/PKU.WHXB20031203(13) Ding, J. J.; Ding, X. Q.; Zhao, L. F.; Chen, J. S. Acta Phys. -Chim. Sin. 2003, 19, 1108. [丁俊杰, 丁晓琴, 赵立峰,陈冀胜. 物理化学学报, 2003, 19, 1108.] doi: 10.3866/PKU.WHXB20031203
14. [14]
  (14) Xiao, J. F.; Guo, Z. R.; Guo, Y. S.; Chu, F. M.; Sun, P. Y. Acta Chim. Sin. 2005, 30 (8), 213. [肖景发, 郭宗儒, 郭彦伸, 褚凤鸣, 孙飘扬. 化学学报, 2005, 30 (8), 213.](14) Xiao, J. F.; Guo, Z. R.; Guo, Y. S.; Chu, F. M.; Sun, P. Y. Acta Chim. Sin. 2005, 30 (8), 213. [肖景发, 郭宗儒, 郭彦伸, 褚凤鸣, 孙飘扬. 化学学报, 2005, 30 (8), 213.]
15. [15]
  (15) Cramer, R. D.; Patterson, D. E.; Bunce, J. D. J. Am. Chem. Soc.1988, 110, 5959. doi: 10.1021/ja00226a005(15) Cramer, R. D.; Patterson, D. E.; Bunce, J. D. J. Am. Chem. Soc.1988, 110, 5959. doi: 10.1021/ja00226a005
16. [16]
  (16) Klebe, G.; Abraham, U.; Mietzner, T. J. Med. Chem. 1994, 37,4130. doi: 10.1021/jm00050a010(16) Klebe, G.; Abraham, U.; Mietzner, T. J. Med. Chem. 1994, 37,4130. doi: 10.1021/jm00050a010
17. [17]
  (17) Wei, Z.; Zhang, H.; Cui,W.; Ji, M. J. Acta Phys. -Chim. Sin.2009, 25, 890. [魏卓, 张怀, 崔巍, 计明娟. 物理化学学报, 2009, 25, 890.] doi: 10.3866/PKU.WHXB20090409(17) Wei, Z.; Zhang, H.; Cui,W.; Ji, M. J. Acta Phys. -Chim. Sin.2009, 25, 890. [魏卓, 张怀, 崔巍, 计明娟. 物理化学学报, 2009, 25, 890.] doi: 10.3866/PKU.WHXB20090409
18. [18]
  (18) Wu, Y.;Wang, Y.; Zhang, A. Q.; Yu, H. X.;Wang, L. S. Chin. Sci. Bull. 2010, 55, 34. [邬旸, 王雍, 张爱茜, 于红霞, 王连生. 科学通报, 2010, 55, 34.](18) Wu, Y.;Wang, Y.; Zhang, A. Q.; Yu, H. X.;Wang, L. S. Chin. Sci. Bull. 2010, 55, 34. [邬旸, 王雍, 张爱茜, 于红霞, 王连生. 科学通报, 2010, 55, 34.]
19. [19]
  (19) Kubinyi, H. Drug Discov. Today 1997, 11, 457.(19) Kubinyi, H. Drug Discov. Today 1997, 11, 457.
20. [20]
  (20) Kubinyi, H. Drug Discov. Today 1997, 12, 538.(20) Kubinyi, H. Drug Discov. Today 1997, 12, 538.
21. [21]
  (21) SYBYL Molecular Modeling Software; Tripos Inc.: St. Louis,MO, 2002.(21) SYBYL Molecular Modeling Software; Tripos Inc.: St. Louis,MO, 2002.
22. [22]
  (22) McIntosh, A. R.; Bookstein, F. L.; Haxby, J. V.; Grady, C. L.Neuroimage 1996, 3, 143. doi: 10.1006/nimg.1996.0016(22) McIntosh, A. R.; Bookstein, F. L.; Haxby, J. V.; Grady, C. L.Neuroimage 1996, 3, 143. doi: 10.1006/nimg.1996.0016
23. [23]
  (23) Wold, S.; Sjöström, M.; Eriksson, L. Chemom. Intell. Lab. Syst.2001, 58, 109. doi: 10.1016/S0169-7439(01)00155-1(23) Wold, S.; Sjöström, M.; Eriksson, L. Chemom. Intell. Lab. Syst.2001, 58, 109. doi: 10.1016/S0169-7439(01)00155-1
24. [24]
  (24) Cramer, R. D. Perspect Drug Discov. Des. 1993, 1, 269.(24) Cramer, R. D. Perspect Drug Discov. Des. 1993, 1, 269.
25. [25]
  (25) Bush, B. L., Jr.; Nachbar, R. B. J. Comput. Aided Mol. Des.1993, 7, 587. doi: 10.1007/BF00124364(25) Bush, B. L., Jr.; Nachbar, R. B. J. Comput. Aided Mol. Des.1993, 7, 587. doi: 10.1007/BF00124364
26. [26]
  (26) Tropsha, A.; lbraikh, A. J. Mol. Graph. Model. 2002, 20, 269.doi: 10.1016/S1093-3263(01)00123-1(26) Tropsha, A.; lbraikh, A. J. Mol. Graph. Model. 2002, 20, 269.doi: 10.1016/S1093-3263(01)00123-1
27. [27]
  (27) http://www.rcsb.org(27) http://www.rcsb.org
28. [28]
  (28) Phan, J.; Koli, S.; Minor,W.; Dunlap, R. B.; Berger, S. H.;Lebioda, L. Biochemistry 2001, 40, 1897. doi: 10.1021/bi002413i(28) Phan, J.; Koli, S.; Minor,W.; Dunlap, R. B.; Berger, S. H.;Lebioda, L. Biochemistry 2001, 40, 1897. doi: 10.1021/bi002413i
29. [29]
  (29) Pettersen, E. F.; ddard, T. D.; Huang, C. C.; Couch, G. S.;Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. J. Comput. Chem.2004, 25, 1605.(29) Pettersen, E. F.; ddard, T. D.; Huang, C. C.; Couch, G. S.;Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. J. Comput. Chem.2004, 25, 1605.
30. [30]
  (30) Lang, P. T.; Moustakas, D.; Brozell, S.; Carrascal, N.;Mukherjee, S.; Pegg, S.; Raha, K.; Shivakumar, D.; Rizzo, R.;Case, D.; Shoichet, B.; Kuntz, I. DOCK, Version 6.1; Universityof California, San Francisco, USA, 2006.(30) Lang, P. T.; Moustakas, D.; Brozell, S.; Carrascal, N.;Mukherjee, S.; Pegg, S.; Raha, K.; Shivakumar, D.; Rizzo, R.;Case, D.; Shoichet, B.; Kuntz, I. DOCK, Version 6.1; Universityof California, San Francisco, USA, 2006.
31. [31]
  (31) Clark, M.; Cramer, R. D.; Jones, D. M.; Patterson, D. E.;Simeroth, P. E. Tetrahedron Comput. Method 1990, 3 (1), 47.doi: 10.1016/0898-5529(90)90120-W(31) Clark, M.; Cramer, R. D.; Jones, D. M.; Patterson, D. E.;Simeroth, P. E. Tetrahedron Comput. Method 1990, 3 (1), 47.doi: 10.1016/0898-5529(90)90120-W
32. [32]
  (32) Wang, B. L.;Wang, J. G.; Ma, Y.; Li, Z. M.; Li, Y. H.;Wang, S.H. Acta Chim. Sin. 2006, 64 (13), 1373. [王宝雷, 王建国,马翼, 李正名, 李永红, 王素华. 化学学报, 2006, 64 (13),1373.]
  (32) Wang, B. L.;Wang, J. G.; Ma, Y.; Li, Z. M.; Li, Y. H.;Wang, S.H. Acta Chim. Sin. 2006, 64 (13), 1373. [王宝雷, 王建国,马翼, 李正名, 李永红, 王素华. 化学学报, 2006, 64 (13),1373.]

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1.
沈阳化工大学材料科学与工程学院沈阳 110142

五元杂环并嘧啶类胸苷酸合成酶抑制剂的构效关系和分子对接

English

QSAR and Molecular Docking on Five-Membered Heterocyclopyrimidines as Thymidylate Synthase Inhibitors

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通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

五元杂环并嘧啶类胸苷酸合成酶抑制剂的构效关系和分子对接

English

QSAR and Molecular Docking on Five-Membered Heterocyclopyrimidines as Thymidylate Synthase Inhibitors

CCS Chemistry：嵌段共聚物自组装成 “三明治”二维有机材料，实现纳米级压力传感功能

CCS Chemistry：颜徐州、鲍哲南： 你的皮肤可能是一片SPMs

CCS Chemistry：工作高效不疲劳，只须让催化剂动起来

CCS Chemistry：静电组装导向聚合- 聚电解质纳米凝胶量化制备新策略

CCS Chemistry：金黄色葡萄球菌醛基脱氢酶是如何识别特异性底物的？

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