人类腺苷受体A3亚型拮抗剂的构效关系分析

doi:10.3866/PKU.WHXB201203272

物理化学学报 >> 2012, Vol. 28 >> Issue (06): 1509-1519.doi: 10.3866/PKU.WHXB201203272

人类腺苷受体A₃亚型拮抗剂的构效关系分析

乔康, 曾凌晓, 金宏威, 刘振明, 张亮仁

北京大学药学院, 天然药物及仿生药物国家重点实验室, 北京 100191

收稿日期:2012-02-22 修回日期:2012-03-27 发布日期:2012-05-17
通讯作者: 金宏威,张亮仁 E-mail:liangren@bjmu.edu.cn; jinhw@bjmu.edu.cn
基金资助:
国家自然科学基金(20972010)和教育部博士点基金(20090001120049)资助项目

QSAR Analysis of Human Adenosine A₃ Receptor Antagonists

QIAO Kang, ZENG Ling-Xiao, JIN Hong-Wei, LIU Zhen-Ming, ZHANG Liang-Ren

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, P. R. China

Received:2012-02-22 Revised:2012-03-27 Published:2012-05-17
Contact: JIN Hong-Wei, ZHANG Liang-Ren E-mail:liangren@bjmu.edu.cn; jinhw@bjmu.edu.cn
Supported by:
The project was supported by the National Natural Science Foundation of China (20972010) and Doctoral Fund of Ministry of Education of China (20090001120049).

摘要/Abstract

摘要： 构建人类腺苷受体A₃亚型药效团模型和三维蛋白结构模型用于作用模式研究. 以18 个来源于文献具有腺苷受体A₃亚型拮抗活性的化合物作为训练集, 使用HypoGen方法构建药效团模型. 通过同源模建和分子动力学模拟构建了人类腺苷受体A₃亚型的三维蛋白模型, 并利用PROCHECK方法评估该模型的合理性, 对所得的结构使用分子对接程序进行作用模式分析, 药效团模型和同源模建结果相互匹配较好. 使用新药效团模型对MDL药物数据库(MDDR)中包含的约120000 个化合物进行虚拟筛选, 得到了8 个候选化合物, 用于进一步的生物学评价和活性测定. 本工作对于人类腺苷受体A₃亚型拮抗剂的设计和抗哮喘药物的研发具有一定的理论指导和应用价值.

关键词: 药效团模型, 同源模建, 分子对接, 虚拟筛选, 人类腺苷受体A₃亚型, 拮抗剂

Abstract: Ligand-based and receptor-based methods were implemented together to investigate the binding modes of human adenosine A₃ antagonists. First, pharmacophore models were developed using the HypoGen program with a training set of 18 diverse human adenosine A₃ receptor antagonists from literature. Meanwhile, the three-dimensional structure of A₃ receptor was modeled by homology modeling and molecular dynamics, and validated by PROCHECK. Molecular docking was conducted further to investigate receptor-ligand interactions. The pharmacophore model and homology models of A₃ receptor matched well, allowing some important information to be obtained. One of the new pharmacophore models was used to screen the MDL drug database report (MDDR) including about 120000 compounds. As a result, eight candidate compounds that can be used for biological evaluation were discovered. These findings are important for the development and discovery of novel selective A₃ antagonists and antiasthmatic compounds.

Key words: Pharmacophore modeling, Homology modeling, Molecular docking, Virtual screening, Human adenosine A₃ receptor, Antagonists

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乔康, 曾凌晓, 金宏威, 刘振明, 张亮仁. 人类腺苷受体A₃亚型拮抗剂的构效关系分析[J]. 物理化学学报, 2012, 28(06), 1509-1519. doi: 10.3866/PKU.WHXB201203272

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. doi: 10.3866/PKU.WHXB201203272

链接本文: https://www.whxb.pku.edu.cn/CN/10.3866/PKU.WHXB201203272

https://www.whxb.pku.edu.cn/CN/Y2012/V28/I06/1509

参考文献

(1) Stone, T. W. Purines: Pharmacology and Physiological Roles; MacMillan: London, 1985.
(2) Li, S. Y. Adenosine: A Procursor of Atp, with Cytoprotective and Cytotoxic Effects. Ph. D. Dissertation, Guangzhou Medical University, Guangdong, 2010. [李舒珏. 腺苷的细胞保护和细胞毒性作用[D]. 广东: 广州医学院, 2010.]
(3) Ralevic, V.; Burnstock, G. Pharmacol. Rev. 1998, 50, 413.
(4) Fredholm, B. B.; Ijzerman, A. P.; Jacobson, K. A.; Linden, J.; Müller, C. E. Pharmacol. Rev. 2001, 53, 527.
(5) Dixon, A. K.; Gubitz, A. K.; Sirinathsinghji, D. J.; Richardson, P. J.; Freeman, T. C. Br. J. Pharmacol. 1996, 118, 1461.
(6) Ramkumar, V.; Nie, Z.; Rybak, L. P. Trends Pharmacol. Sci. 1995, 16, 283.  doi: 10.1016/S0165-6147(00)89051-3
(7) Carruthers, A. M.; Fozard, J. R. Eur. J. Pharmacol. 1993, 250, 185.  doi: 10.1016/0014-2999(93)90641-T
(8) Ferre, S.; Fredholm, B. B.; Morelli, M.; Popoli, P.; Fuxe, K. Trends Neurosci. 1997, 20, 482.  doi: 10.1016/S0166-2236(97)01096-5
(9) Xu, X. J.; Hou, T. J.; Qiao, X. B.; Zhang, W. Computer-aided Drug Molecular Design; Chemical Industry Press: Beijing, 2004; pp 295-300. [徐筱杰, 侯廷军, 乔学斌, 章威. 计算机辅助药物分子设计. 北京: 化学工业出版社, 2004: 295-300.]
(10) Guo, Z. R. Drug Molecular Design; Science Press: Beijing, 2005; pp 372-373. [郭宗儒. 药物分子设计. 北京: 科学出版社, 2005: 372-373.]
(11) Osman, F. G.; Pharmacophore Perception, Development, and Use in Drug Design; International University Line: La Jolla, 2000; pp 8-9.
(12) PROTEIN DATA BANK. http://www.rcsb.org (accessed Mar. 26, 2012).
(13) Expasy Bioinformatics Resource Portal. http://expasy.org/sprot/ (accessed Mar. 26, 2012).
(14) Discovery Studio Software. Version 2.5; San Diego: Accelrys. Inc., 2009.
(15) Berendsen, H. J. C.; van der Spoel, D.; van Drunen, R. Comp. Phys. Commun. 1995, 91, 43.  doi: 10.1016/0010-4655(95)00042-E
(16) Lindahl, E.; Hess, B.; van der Spoel, D. J. Mol. Model 2001, 7, 306.
(17) Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267, 727.  doi: 10.1006/jmbi.1996.0897
(18) Baraldi, P. G.; Cacciari, B.; Moro, S.; Spalluto, G.; Pastorin, G.; Da Ros T.; Klotz, K. N.; Varani, K.; Gessi, S.; Borea, P. A. J. Med. Chem. 2002, 45, 770.  doi: 10.1021/jm0109614
(19) Borghini, A.; Pietra, D.; Domenichelli, P.; Bianucci, A. M. Bioorg. Med. Chem. 2005, 13, 5330.  doi: 10.1016/j.bmc.2005.05.041
(20) Baraldi, P. G.; Preti, D.; Tabrizi, M. A.; Romagnoli, R.; Saponaro, G. Baraldi, S.; Botta, M.; Bernardini, C.; Tafi, A.; Tuccinardi, T.; Martinelli, A.; Varani, K.; Borea, P. A. Bioorg. Med. Chem. 2008, 16, 10281.  doi: 10.1016/j.bmc.2008.10.049
(21) Baraldi, P. G.; Preti, D.; Tabrizi, M. A.; Fruttarolo, F.; Romagnoli, R.; Zaid, N.A.; Moorman, A. R.; Merighi, S.; Varani, K.; Borea, P. A. J. Med. Chem. 2005, 48, 4697
(22) Melman, A.; Wang, B.; Joshi, B. V.; Gao, Z. G.; Castro, S.; Heller, C. L.; Kim, S. K.; Jeong, L. S.; Jacobson, K. A. Bioorg. Med. Chem. 2008, 16, 8546.  doi: 10.1016/j.bmc.2008.08.007
(23) Okamura, T.; Kurogi, Y.; Nishikawa, H.; Hashimoto, K.; Fujiwara, H.; Nagao, Y. J. Med.Chem. 2002, 45, 3703.  doi: 10.1021/jm010570p
(24) Baraldi, P. G.; Tabrizi, M. A.; Preti, D.; Bovero, A.; Fruttarolo, F.; Romagnoli, R.; Zaid, N. A.; Moorman, A. R.; Varani, K.; Borea, P. A. J. Med. Chem. 2005, 48, 5001.  doi: 10.1021/jm050125k
(25) Baraldi, P. G.; Borea, P. A. Trends Pharmacol. Sci. 2000, 21, 456.  doi: 10.1016/S0165-6147(00)01581-9
(26) Chen, X.; Liu, X. X.; Huang, H.; Hu, H. H.; Jiang, F. C. Acta Phys. -Chim. Sin. 2008, 24, 281. [陈曦, 刘心霞, 黄慧, 胡慧慧, 姜凤超. 物理化学学报, 2008, 24, 281.]
(27) Huang, W. H.; Hu, C. Q.; Liao, Y.; Sheng, R.; Hu, Y. Z. Acta Chim. Sin. 2008, 66, 1889. [黄文海, 胡纯琦, 廖勇, 盛荣, 胡永洲. 化学学报, 2008, 66, 1889.]
(28) Bao, H. J.; Tang, Y. L.; Xu, X. J.; Xiang, J. F.; Zheng, Z. H.; Lu, X. H. Chem. J. Chin. Univ. 2010, 31, 938. [鲍红娟, 唐亚林, 徐筱杰, 向俊峰, 郑智慧, 路新华. 高等学校化学学报, 2010, 31, 938.]
(29) Osman, F. G.; Pharmacophore Perception, Development, and Use in Drug Design; International University Line: La Jolla, 2000; p 174.
(30) Bao, H. J.; Zhang, Y. L.; Qiao, Y. J. Chem. J. Chin. Univ. 2008, 29, 1125. [鲍红娟, 张燕玲, 乔延江. 高等学校化学学报, 2008, 29, 1125.]
(31) Osman, F. G.; Pharmacophore Perception, Development, and Use in Drug Design; International University Line: La Jolla, 2000; pp 259-260.
(32) Wei, B. Q.; Baase, W. A.; Weaver, L. H.; Mattews, B. W.; Shoichet, B. K. J. Mol. Biol. 2002, 322, 339.  doi: 10.1016/S0022-2836(02)00777-5
(33) Hevener, K. E.; Zhao, W.; Ball, D. M.; Babaoglu, K.; Qi, J. J.; White, S. W.; Lee, R. E. J. Chem. Inf. Model 2009, 49, 444.  doi: 10.1021/ci800293n
(34) Truchon, J. F.; Bayly, C. I. J. Chem. Inf. Model 2007, 47, 488.  doi: 10.1021/ci600426e
(35) Ke, Y. R.; Jin, H. W.; Liu, Z. M.; Zhang, L. R. Acta Phys. -Chim. Sin. 2010, 26, 2833. [柯艳蓉, 金宏威, 刘振明, 张亮仁. 物理化学学报, 2010, 26, 2833.]
(36) Bao, H. J.; Zhang, Y. L.; Qiao, Y. J. Acta Phys. -Chim. Sin.2008, 24, 301. [鲍红娟, 张燕玲, 乔延江. 物理化学学报, 2008, 24, 301.]
(37) Morris, A. L.; MacArthur, M. W.; Hutchinson, E. G.; Thornton, J. M. Proteins 1992, 12, 345.  doi: 10.1002/prot.340120407
(38) Manetti, F.; Schenone, S.; Bondavalli, F.; Brullo, C.; Bruno, O.; Ranise, A.; Mosti, L.; Menozzi, G.; Fossa, P.; Trincavelli, M. L.; Martini, C.; Martinelli, A.; Tintori, C.; Botta, M. J. Med. Chem.. 2005, 48, 7172.  doi: 10.1021/jm050407k
(39) Wei, J. The Study of Pharmacophore Modeling and Molecular Docking for Adenosine Receptor Antagonists. Ph. D. Dissertation, Tianjin University, Tianjin, 2007. [魏静. 腺苷受体拮抗剂药效团模建和分子对接研究[D]. 天津: 天津大学, 2007.]
(40) Cheng, F.; Xu, Z.; Liu, G.; Tang, Y. Eur. J. Med. Chem. 2010, 45, 3459.  doi: 10.1016/j.ejmech.2010.04.039
(41) Tafi, A.; Bernardini, C.; Botta, M.; Corelli, F.; Andreini, M.; Martinelli, A.; Ortore, G.; Baraldi, P. G.; Fruttarolo, F.; Borea, P. A.; Tuccinardi, T. J. Med. Chem. 2006, 49, 4085.  doi: 10.1021/jm051112+

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人类腺苷受体A₃亚型拮抗剂的构效关系分析

QSAR Analysis of Human Adenosine A₃ Receptor Antagonists

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