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

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: 15 November 2012
Fund Project: 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)

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.
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
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
3. [3]
  (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
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
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
7. [7]
  (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
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
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
11. [11]
  (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.]
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
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.]
15. [15]
  (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
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
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.]
19. [19]
  (19) Kubinyi, H. Drug Discov. Today 1997, 11, 457.
20. [20]
  (20) Kubinyi, H. Drug Discov. Today 1997, 12, 538.
21. [21]
  (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
23. [23]
  (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.
25. [25]
  (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
27. [27]
  (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
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.
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.
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
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.]
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