Please wait a minute...
Acta Phys. Chim. Sin.  2013, Vol. 29 Issue (02): 431-438    DOI: 10.3866/PKU.WHXB201211151
BIOPHYSICAL CHEMISTRY     
QSAR and Molecular Docking on Five-Membered Heterocyclopyrimidines as Thymidylate Synthase Inhibitors
KANG Cong-Min1, ZHAO Xu-Hao1, WANG Xin-Yu1, CHENG Jia-Gao2, LÜ Ying-Tao1
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
Download:   PDF(993KB) Export: BibTeX | EndNote (RIS)      

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 (Qext2) was 0.85. And with the CoMSIA model, the corresponding q2, R2, and Qext2 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 good 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 wordsFive-membered heterocyclopyrimidine derivative      Three dimensional quantitative structure-activity relationship      Comparative molecular field analysis      Comparative molecular similarity indices analysis      Molecular docking     
Received: 27 August 2012      Published: 15 November 2012
MSC2000:  O641  
Fund:  

The project was supported by the National Natural Science Foundation of China (21072111, 21172070, 21272131) and Shandong Provincial Natural Science Foundation, China (ZR2011BM015).

Cite this article:

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. Acta Phys. Chim. Sin., 2013, 29(02): 431-438.

URL:

http://www.whxb.pku.edu.cn/Jwk_wk/wlhx/10.3866/PKU.WHXB201211151     OR     http://www.whxb.pku.edu.cn/Jwk_wk/wlhx/Y2013/V29/I02/431

(1) Doan, L. T.; Martucci,W. E.; Vargo, M. A.; Atreya, C. E.;Anderson, K. S. Biochemistry 2007, 46, 8379. doi: 10.1021/bi700531r
(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) Gangjee, A.; Kurup, S.; Namjoshi, O. Curr. Pharm. Des. 2007,13, 609. doi: 10.2174/138161207780162827
(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) 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) 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) Gangjee, A.; Li,W.; Yang, J.; Kisliuk, R. L. J. Med. Chem.2008, 51, 68. doi: 10.1021/jm701052u
(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) 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) 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) Kunal, R.; Thomas, L. J. Bioorg. Med. Chem. 2005, 13 (8),2967. doi: 10.1016/j.bmc.2005.02.003
(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) 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) 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) Cramer, R. D.; Patterson, D. E.; Bunce, J. D. J. Am. Chem. Soc.1988, 110, 5959. doi: 10.1021/ja00226a005
(16) Klebe, G.; Abraham, U.; Mietzner, T. J. Med. Chem. 1994, 37,4130. doi: 10.1021/jm00050a010
(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) 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) Kubinyi, H. Drug Discov. Today 1997, 11, 457.
(20) Kubinyi, H. Drug Discov. Today 1997, 12, 538.
(21) SYBYL Molecular Modeling Software; Tripos Inc.: St. Louis,MO, 2002.
(22) McIntosh, A. R.; Bookstein, F. L.; Haxby, J. V.; Grady, C. L.Neuroimage 1996, 3, 143. doi: 10.1006/nimg.1996.0016
(23) Wold, S.; Sjöström, M.; Eriksson, L. Chemom. Intell. Lab. Syst.2001, 58, 109. doi: 10.1016/S0169-7439(01)00155-1
(24) Cramer, R. D. Perspect Drug Discov. Des. 1993, 1, 269.
(25) Bush, B. L., Jr.; Nachbar, R. B. J. Comput. Aided Mol. Des.1993, 7, 587. doi: 10.1007/BF00124364
(26) Tropsha, A.; Golbraikh, A. J. Mol. Graph. Model. 2002, 20, 269.doi: 10.1016/S1093-3263(01)00123-1
(27) http://www.rcsb.org
(28) Phan, J.; Koli, S.; Minor,W.; Dunlap, R. B.; Berger, S. H.;Lebioda, L. Biochemistry 2001, 40, 1897. doi: 10.1021/bi002413i
(29) Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.;Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. J. Comput. Chem.2004, 25, 1605.
(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) 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) 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.]

[1] DENG Ying-Chun, LIU Qing, HUANG Qiang. Molecular Docking of Human-Like Receptor to Hemagglutinins of Avian Influenza A Viruses[J]. Acta Phys. Chim. Sin., 2017, 33(3): 633-641.
[2] DENG Yu-Ling, YU Lu, HUANG Qiang. A Multi-Target Docking System of Human Kinome[J]. Acta Phys. Chim. Sin., 2016, 32(9): 2355-2363.
[3] XU Shi-Wen, LIN Dong-Qiang, YAO Shan-Jing. Evaluation of Molecular Binding Modes on Site II of Human Serum Albumin[J]. Acta Phys. Chim. Sin., 2016, 32(7): 1819-1828.
[4] LIN Feng, FU Xin-Mei, WANG Chao, JIANG Si-Yu, WANG Jing-Hui, ZHANG Shu-Wei, YANG Ling, LI Yan. QSAR, Molecular Docking and Molecular Dynamics of 3C-like Protease Inhibitors[J]. Acta Phys. Chim. Sin., 2016, 32(11): 2693-2708.
[5] LUO Qi-Yao, WANG Zi-Yun, JIN Hong-Wei, LIU Zhen-Ming, ZHANG Liang-Ren. Improved Docking-Based Virtual Screening Using the Score Correction Strategy for Specific Endothelial Lipase Inhibitors Identification[J]. Acta Phys. Chim. Sin., 2016, 32(10): 2606-2619.
[6] ZHANG Shu-Zhen, ZHENG Chao, ZHU Chang-Jin. Molecular Docking and Receptor-Based 3D-QSAR Studies on Aromatic Thiazine Derivatives as Selective Aldose Reductase Inhibitors[J]. Acta Phys. Chim. Sin., 2015, 31(12): 2395-2404.
[7] LIU Hai-Chun, LU Shuai, RAN Ting, ZHANG Yan-Min, XU Jin-Xing, XIONG Xiao, XU An-Yang, LU Tao, CHEN Ya-Dong. Accurate Activity Predictions of B-Raf Type II Inhibitors via Molecular Docking and QSAR Methods[J]. Acta Phys. Chim. Sin., 2015, 31(11): 2191-2206.
[8] CHEN Zheng-Jun, JIANG Qing-Lin, HE Gu, HAN Bo, GUO Li. Multicomplex-Based Pharmacophore and QSAR of Aryl-Sulfamides as Pyruvate Kinase M2 Activators[J]. Acta Phys. Chim. Sin., 2013, 29(08): 1793-1803.
[9] BAI Shu, ZHOU Rong, LIU Fu-Feng. Rational Design of Affinity Ligand for the Oriented Immobilization of Trypsin[J]. Acta Phys. Chim. Sin., 2013, 29(02): 439-448.
[10] HUANG Yang-Yu, YANG Xiu-Feng, LI Hao-Tian, JI Xiao-Feng, CHENG Hong-Li, ZHAO Yun-Jie, GUO Da-Chuan, LI Lin, LIU Shi-Yong. Protein-RNA Interaction Interface Prediction and Design[J]. Acta Phys. Chim. Sin., 2012, 28(10): 2390-2400.
[11] QIAO Kang, ZENG Ling-Xiao, JIN Hong-Wei, LIU Zhen-Ming, ZHANG Liang-Ren. QSAR Analysis of Human Adenosine A3 Receptor Antagonists[J]. Acta Phys. Chim. Sin., 2012, 28(06): 1509-1519.
[12] SHEN Tao, DU Feng-Pei, LIU Ting, YAO Guang-Wei, WU Zheng, FANG Meng-Meng, XU Xiao-Jie, LU Hui-Zhe. Molecular Simulation of the Interaction between Imidazole Glycerol Phosphate Dehydrase and Nitrogen-Containing Heterocyclic Phosphate Inhibitors[J]. Acta Phys. Chim. Sin., 2011, 27(08): 1831-1838.
[13] ZHANG Yuan, CHEN Ya-Dong, YOU Qi-Dong, ZOU Li-Yun, YANG Yan. Homology Modeling and Molecular Docking Studies on the Selectivity of HDAC1/HDAC8[J]. Acta Phys. Chim. Sin., 2010, 26(06): 1676-1686.
[14] ZHENG Chun-Song, XU Xiao-Jie, LIU Xian-Xiang, YE Hong-Zhi. Computational Pharmacology of Jingzhi Tougu Xiaotong Granule in Preventing and Treating Osteoarthritis[J]. Acta Phys. Chim. Sin., 2010, 26(03): 775-783.
[15] LI Bo, LIU Ming, HU Wen-Xiang. Molecular Docking and Molecular Dynamics Simulations of Fentanyl Analogs Binding to μ-Opioid Receptors[J]. Acta Phys. Chim. Sin., 2010, 26(01): 206-214.