A<sub>1</sub>腺苷受体的同源模建及其结构验证

引用本文: 柯艳蓉, 金宏威, 刘振明, 张亮仁. A₁腺苷受体的同源模建及其结构验证[J]. 物理化学学报, 2010, 26(10): 2833-2839. doi: 10.3866/PKU.WHXB20100916 shu

Citation: KE Yan-Rong, JIN Hong-Wei, LIU Zhen-Ming, ZHANG Liang-Ren. Homology Modeling and Structure Validation of the Adenosine A₁ Receptor[J]. Acta Physico-Chimica Sinica, 2010, 26(10): 2833-2839. doi: 10.3866/PKU.WHXB20100916 shu

A₁腺苷受体的同源模建及其结构验证

摘要:

采用同源模建的方法构建了A₁腺苷受体的三维结构, 并与拮抗剂分子DPCPX对接, 将得到的复合物结构进行5 ns的分子动力学模拟, 以最后2 ns 的平均结构和平衡后抽取的11 帧构象共12 个蛋白结构为研究对象,用包含52 个活性分子和1000个诱饵分子的测试库,分别通过DOCK、VINA 和 LD 三种对接软件进行评价,最终得出合理的蛋白质模型.根据top10%的富集因子(EF)和ROC 曲线下面积(AU-ROC)的计算结果, 我们认为 LD是最适合A₁腺苷受体的对接软件, 而12 个蛋白质结构中F5 和Favg 的三维结构模型比较合理, 可以作为进一步大规模虚拟筛选的模型.

关键词:

English

Homology Modeling and Structure Validation of the Adenosine A₁ Receptor

1.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Health Science Center, Peking University, Beijing 100191, P. R. China
Received Date: 19 May 2010
Available Online: 27 September 2010

Abstract:

A three dimensional structure model of the adenosine A₁ receptor was built using homology modeling. The anta nist DPCPX was docked into the model protein to form a receptor-ligand complex. A molecular dynamics simulation over 5 ns was performed for this complex. We selected 12 protein structures, including the average structure obtained from the last 2 ns of the simulation and 11 frames extracted after equilibration for the study. A database comprising 52 active anta nists and 1000 decoys was then docked into the 12 protein models using DOCK, VINA, and LD software packages and these molecules were ranked by their docking scores. The best model protein with the highest enrichment factor (EF) and the largest area under the ROC (AU-ROC) was chosen for further study. The results from the enrichment factor at 10%of the ranked database (EF₁₀) and AU-ROC calculations indicate that LD is the best virtual screening software for the adenosine A₁ receptor. LD docking results suggest that optimized adenosine A₁ receptor protein structures, Favg and F5, can be used for virtual screening and for novel design to discover more potent anta nists.

Key words:

1. [1]
  
  1. Ralevic, V.; Burnstock, G. Pharmacol. Rev., 1998, 50: 413
  1. Ralevic, V.; Burnstock, G. Pharmacol. Rev., 1998, 50: 413
2. [2]
  2. Müller, C. E.; Stein, B. Curr. Pharm. Design, 1996, 2: 5012. Müller, C. E.; Stein, B. Curr. Pharm. Design, 1996, 2: 501
3. [3]
  3. Poulsen, S. A.; Quinn, R. J. Bioorg. Med. Chem., 1998, 6: 6193. Poulsen, S. A.; Quinn, R. J. Bioorg. Med. Chem., 1998, 6: 619
4. [4]
  4. Müller, C. E. Expert. Opin. Ther. Pat., 1997, 7: 4194. Müller, C. E. Expert. Opin. Ther. Pat., 1997, 7: 419
5. [5]
  5. Hess, S. Expert. Opin. Ther. Pat., 2001, 11: 15335. Hess, S. Expert. Opin. Ther. Pat., 2001, 11: 1533
6. [6]
  6. Maemoto, T. J. Pharmacol. Sci., 2004, 96: 426. Maemoto, T. J. Pharmacol. Sci., 2004, 96: 42
7. [7]
  7. Wilcox, C. S.;Welch, W. J.; Schreiner, G. F.; Belardinelli, L. J. Am. Soc. Nephrol., 1999, 10: 7147. Wilcox, C. S.;Welch, W. J.; Schreiner, G. F.; Belardinelli, L. J. Am. Soc. Nephrol., 1999, 10: 714
8. [8]
  8. ttlieb, S. S. Circulation, 2002, 105: 13488. ttlieb, S. S. Circulation, 2002, 105: 1348
9. [9]
  9. Giordanetto, F.; Fossa, P.; Menozzi, G.; Schenone, S.; Bondavalli, F.; Ranise, A.; Mosti, L. J. Comput. Aided Mol. Des., 2003, 17: 399. Giordanetto, F.; Fossa, P.; Menozzi, G.; Schenone, S.; Bondavalli, F.; Ranise, A.; Mosti, L. J. Comput. Aided Mol. Des., 2003, 17: 39
10. [10]
  10. Gutiérrez-de-terán, H.; Centeno, N. B.; Pastor, M.; Sanz, F. Proteins, 2004, 54: 70510. Gutiérrez-de-terán, H.; Centeno, N. B.; Pastor, M.; Sanz, F. Proteins, 2004, 54: 705
11. [11]
  11. Tuccinardi, T.; Ortore, G.; Manera, C.; Saccomanni, G.; Martinelli, M. Euro. J. Med. Chem., 2006, 41: 32111. Tuccinardi, T.; Ortore, G.; Manera, C.; Saccomanni, G.; Martinelli, M. Euro. J. Med. Chem., 2006, 41: 321
12. [12]
  12. Cherezov, V. Science, 2007, 318: 125812. Cherezov, V. Science, 2007, 318: 1258
13. [13]
  13. Yuzlenko, O.; Kiec-Kononowicz, K. J. Comput. Chem., 2009, 30: 1413. Yuzlenko, O.; Kiec-Kononowicz, K. J. Comput. Chem., 2009, 30: 14
14. [14]
  14. Jaakola, V. P. Science, 2008, 322: 121114. Jaakola, V. P. Science, 2008, 322: 1211
15. [15]
  15. http://www.gpcr.org15. http://www.gpcr.org
16. [16]
  16. http://expasy.org/sprot/16. http://expasy.org/sprot/
17. [17]
  17. SYBYL software. Version 6.9. St. Louis: Tripos. Associates. Inc.17. SYBYL software. Version 6.9. St. Louis: Tripos. Associates. Inc.
18. [18]
  18. Discovery Studio software. Version 2.1. San Die : Accelrys. Inc.18. Discovery Studio software. Version 2.1. San Die : Accelrys. Inc.
19. [19]
  19. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol., 1997, 267: 72719. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol., 1997, 267: 727
20. [20]
  20. Barbhaiya, H.; McClain, R.; Ijzerman, A.; Rivkees, S. Mol. Pharmacol., 1996, 50: 163520. Barbhaiya, H.; McClain, R.; Ijzerman, A.; Rivkees, S. Mol. Pharmacol., 1996, 50: 1635
21. [21]
  21. Olah, M. E.; Ren, H.; Ostrowski, J.; Jacobson, K. A.; Stiles, G. L. J. Biol. Chem., 1992, 267: 1076421. Olah, M. E.; Ren, H.; Ostrowski, J.; Jacobson, K. A.; Stiles, G. L. J. Biol. Chem., 1992, 267: 10764
22. [22]
  22. Martinelli, A.; Tuccinardi, T. Mol. Res. Rev., 2008, 28: 24722. Martinelli, A.; Tuccinardi, T. Mol. Res. Rev., 2008, 28: 247
23. [23]
  23. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; et al. Gaussian 03. Revision B.03.Wallingford, CT: Gaussian Inc., 200323. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; et al. Gaussian 03. Revision B.03.Wallingford, CT: Gaussian Inc., 2003
24. [24]
  24. Bayly, C. I.; Cieplak, P.; Cornell, W. D.; Kollman, P. A. J. Phys. Chem., 1993, 97: 1026924. Bayly, C. I.; Cieplak, P.; Cornell, W. D.; Kollman, P. A. J. Phys. Chem., 1993, 97: 10269
25. [25]
  25. Berendsen, H. J. C.; van der Spoel, D.; van Drunen, R. Comp. Phys. Commun., 1995, 91: 4325. Berendsen, H. J. C.; van der Spoel, D.; van Drunen, R. Comp. Phys. Commun., 1995, 91: 43
26. [26]
  26. Lindahl, E.; Hess, B.; van der Spoel, D. J. Mol. Model., 2001, 7: 30626. Lindahl, E.; Hess, B.; van der Spoel, D. J. Mol. Model., 2001, 7: 306
27. [27]
  27. van der Spoel, D.; Buuren, A. R. V.; Tieleman, D. P.; Berendsen, H. J. J. Biomol. NMR, 1996, 8: 22927. van der Spoel, D.; Buuren, A. R. V.; Tieleman, D. P.; Berendsen, H. J. J. Biomol. NMR, 1996, 8: 229
28. [28]
  28. Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.; Dinola, A.; Haak, J. R. J. Chem. Phys., 1984, 81: 368428. Berendsen, H. J. C.; Postma, J. P. M.; van Gunsteren, W. F.; Dinola, A.; Haak, J. R. J. Chem. Phys., 1984, 81: 3684
29. [29]
  29. Hess, B.; Bekker, H.; Berendsen, H. J. C.; Fraaije, J. G. E. M. J. Comput. Chem., 1997, 18: 46329. Hess, B.; Bekker, H.; Berendsen, H. J. C.; Fraaije, J. G. E. M. J. Comput. Chem., 1997, 18: 463
30. [30]
  30. Darden, T.; York, D.; Pedersen, L. J. Chem. Phys., 1993, 98: 1008930. Darden, T.; York, D.; Pedersen, L. J. Chem. Phys., 1993, 98: 10089
31. [31]
  31. Kuntz, I. D.; Blaney, J. M.; Oatley, S. J.; Langridge, R.; Ferrin, T. E. J. Mol. Biol., 1982, 161: 26931. Kuntz, I. D.; Blaney, J. M.; Oatley, S. J.; Langridge, R.; Ferrin, T. E. J. Mol. Biol., 1982, 161: 269
32. [32]
  32. Ewing, T. J. A.; Kuntz, I. D. J. Comput. Chem., 1997, 18: 117532. Ewing, T. J. A.; Kuntz, I. D. J. Comput. Chem., 1997, 18: 1175
33. [33]
  33. Trott, O.; Arthur, J. O. J. Comput. Chem., 2010, 31: 45533. Trott, O.; Arthur, J. O. J. Comput. Chem., 2010, 31: 455
34. [34]
  34. Moro, S.; Gao, Z. G.; Jacobson, K. A.; Spalluto, G. Med. Res. Rev., 2006, 26: 13134. Moro, S.; Gao, Z. G.; Jacobson, K. A.; Spalluto, G. Med. Res. Rev., 2006, 26: 131
35. [35]
  35. Wei, B. Q.; Baase, W. A.;Weaver, L. H.; Mattews, B. W.; Shoichet, B. K. J. Mol. Biol., 2002, 322: 33935. Wei, B. Q.; Baase, W. A.;Weaver, L. H.; Mattews, B. W.; Shoichet, B. K. J. Mol. Biol., 2002, 322: 339
36. [36]
  36. 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: 44436. 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
37. [37]
  37. Truchon, J. F.; Bayly, C. I. J. Chem. Inf. Model., 2007, 47: 488
  37. Truchon, J. F.; Bayly, C. I. J. Chem. Inf. Model., 2007, 47: 488

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1.
沈阳化工大学材料科学与工程学院沈阳 110142

A₁腺苷受体的同源模建及其结构验证

English

Homology Modeling and Structure Validation of the Adenosine A₁ Receptor

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