ω-芋螺毒素的定量构效关系与虚拟筛选

引用本文: 丁俊杰, 丁晓琴, 李大禹, 潘里, 陈冀胜. ω-芋螺毒素的定量构效关系与虚拟筛选[J]. 物理化学学报, 2014, 30(11): 2157-2167. doi: 10.3866/PKU.WHXB201409171 shu

Citation: DING Jun-Jie, DING Xiao-Qin, LI Da-Yu, PAN Li, CHEN Ji-Sheng. Quantitative Structure-Activity Relationship and Virtual Screening of ω-Conotoxins[J]. Acta Physico-Chimica Sinica, 2014, 30(11): 2157-2167. doi: 10.3866/PKU.WHXB201409171 shu

ω-芋螺毒素的定量构效关系与虚拟筛选

摘要:

ω-芋螺毒素属于海洋生物活性多肽, 由24-31 个氨基酸残基组成. 特异性作用于电压敏感的钙离子通道(VGCCs), 能够直接开发成药物或作为先导化合物进行新药开发. 本文应用新型氨基酸残基结构描述符cscales和遗传偏最小二乘算法, 对ω-芋螺毒素进行定量构效关系(QSAR)研究, 并设计、构建了容量为2244 个化合物的N-型和P/Q-型VGCC拮抗剂虚拟组合多肽库, 然后分别采用QSAR模型预测和相似性搜索方法对组合多肽库进行了虚拟筛选. 研究结果表明, 建立的N-型和P/Q-型VGCC拮抗剂QSAR模型均具有较好的预测能力, 交叉验证相关系数(CV-r²)均大于0.89. 主成分分析和聚类分析结果表明, 虚拟组合多肽库中化合物具有较好的结构多样性和差异性. 通过虚拟筛选, 得到了具有高预测活性的6 个N-型和19 个P/Q-型钙离子通道拮抗剂, 为进一步的合成和活性评价奠定了理论基础. 同时, 本文建立的多肽QSAR预测模型和虚拟筛选策略, 为其它多肽类化合物的定量构效关系研究和虚拟筛选提供了参考.

关键词:

English

Quantitative Structure-Activity Relationship and Virtual Screening of ω-Conotoxins

1.
State Key Laboratory of NBC Protection for Civilian, Beijing Institute of Pharmaceutical Chemistry, Beijing 102205, P. R. China
Received Date: 16 July 2014
Available Online: 30 October 2014

Abstract:

ω-Conotoxins are active peptides composed of 24-31 amino acids isolated from venomous marine predatory cone snails. ω-Conotoxins selectively inhibit voltage-gated calcium channels (VGCCs) in nociceptors, so are considered attractive molecules for drug design. In this study, based on a set of new amino acid structure descriptors (c-scales) and genetic partial least squares (G/PLS) regression method, quantitative structureactivity relationship (QSAR) models for N-type and P/Q-type VGCC anta nists of ω-conotoxins were developed. Two virtual polypeptide libraries with 2244 peptides were designed and established for N-type and P/Q-type VGCC anta nists, respectively. Then, based on the biological activities predicted from the constructed QSAR models and chemical similarities to the probes MVIIA and MVIIC, the polypeptide libraries were virtually screened. As a result, the established QSAR models had od predictability (cross- validated correlation coefficient CV-r²>0.89). The structural diversity of the libraries was validated using principal component analysis (PCA) and hierarchical cluster analysis (HCA) approaches. Six N-type and nineteen P/Q-type VGCC anta nists with high selectivity and activity were identified by virtual screening. The results of this study will be valuable for finding highly active polypeptide and non-peptide mimetics. Furthermore, the established polypeptide QSAR models and virtual screening strategy can also be applied to other peptide systems.

Key words:

1. [1]
  
  (1) Vink, S.; Alewood, P. Br. J. Pharmacol. 2012, 167, 970. doi: 10.1111/j.1476-5381.2012.02082.x
  (1) Vink, S.; Alewood, P. Br. J. Pharmacol. 2012, 167, 970. doi: 10.1111/j.1476-5381.2012.02082.x
2. [2]
  (2) Schroeder, C. I.; Lewis, R. J. Mar. Drugs 2006, 4, 193. doi: 10.3390/md403193(2) Schroeder, C. I.; Lewis, R. J. Mar. Drugs 2006, 4, 193. doi: 10.3390/md403193
3. [3]
  (3) Tetsuyuki,W.; Junichi, A.; Takeshi, M.; Takashi, M.; Seiji, I. Neurochem. Res. 2003, 28, 705. doi: 10.1023/A:1022805615926(3) Tetsuyuki,W.; Junichi, A.; Takeshi, M.; Takashi, M.; Seiji, I. Neurochem. Res. 2003, 28, 705. doi: 10.1023/A:1022805615926
4. [4]
  (4) Lewis, R. J.; Dutertre, S.; Vetter, I.; Christie, M. J. Pharmacol. Rev. 2012, 64, 259.(4) Lewis, R. J.; Dutertre, S.; Vetter, I.; Christie, M. J. Pharmacol. Rev. 2012, 64, 259.
5. [5]
  (5) Tetsuyuki,W.; Takashi, I.; Akinori, K.; Masayuki, X. M.; Yasuo, M.; Keiji, I.; Seiji, I. Neurochem. Res. 2005, 30, 1045. doi: 10.1007/s11064-005-7046-6(5) Tetsuyuki,W.; Takashi, I.; Akinori, K.; Masayuki, X. M.; Yasuo, M.; Keiji, I.; Seiji, I. Neurochem. Res. 2005, 30, 1045. doi: 10.1007/s11064-005-7046-6
6. [6]
  (6) Obafemi, A.; Roth, B. Pain Med. 2013, 14, 447. doi: 10.1111/pme.2013.14.issue-3(6) Obafemi, A.; Roth, B. Pain Med. 2013, 14, 447. doi: 10.1111/pme.2013.14.issue-3
7. [7]
  (7) Bourinet, E.; Zamponi, G.W. Curr. Top. Med. Chem. 2005, 5, 539. doi: 10.2174/1568026054367610(7) Bourinet, E.; Zamponi, G.W. Curr. Top. Med. Chem. 2005, 5, 539. doi: 10.2174/1568026054367610
8. [8]
  (8) Lynch, S. S.; Cheng, C. M.; Yee, J. L. Ann. Pharmacother. 2006, 40, 1293. doi: 10.1345/aph.1G584(8) Lynch, S. S.; Cheng, C. M.; Yee, J. L. Ann. Pharmacother. 2006, 40, 1293. doi: 10.1345/aph.1G584
9. [9]
  (9) Alicino, I.; Giglio, M.; Manca, F.; Bruno, F.; Puntillo, F. Pain 2012, 153, 245. doi: 10.1016/j.pain.2011.10.002(9) Alicino, I.; Giglio, M.; Manca, F.; Bruno, F.; Puntillo, F. Pain 2012, 153, 245. doi: 10.1016/j.pain.2011.10.002
10. [10]
  (10) Sanford, M. CNS Drugs 2013, 27, 989. doi: 10.1007/s40263-013-0107-5(10) Sanford, M. CNS Drugs 2013, 27, 989. doi: 10.1007/s40263-013-0107-5
11. [11]
  (11) Sasaki, T.; Kobayashi, K.; Kohno, T.; Sato, K. FEBS Lett. 2000, 466, 125. doi: 10.1016/S0014-5793(99)01772-X(11) Sasaki, T.; Kobayashi, K.; Kohno, T.; Sato, K. FEBS Lett. 2000, 466, 125. doi: 10.1016/S0014-5793(99)01772-X
12. [12]
  (12) Wang, C. Z.; Jiang, H.; Qi, Z.W. Prog. Biochem. Biophys. 2003, 30, 537. [王承忠, 蒋辉, 戚正武. 生物化学与生物物理进展, 2003, 30, 537.](12) Wang, C. Z.; Jiang, H.; Qi, Z.W. Prog. Biochem. Biophys. 2003, 30, 537. [王承忠, 蒋辉, 戚正武. 生物化学与生物物理进展, 2003, 30, 537.]
13. [13]
  (13) Kolosov, A.; Aurini, L.;Williams, E. D.; Cooke, I.; odchild, C. S. Pain Med. 2011, 12, 923. doi: 10.1111/pme.2011.12.issue-6(13) Kolosov, A.; Aurini, L.;Williams, E. D.; Cooke, I.; odchild, C. S. Pain Med. 2011, 12, 923. doi: 10.1111/pme.2011.12.issue-6
14. [14]
  (14) Fedosova, A. E.; Moshkovskiic, S. A.; Kuznetsovac, K. G.; Oliverab, B. M. Biochemistry-Moscow+Series B: Biomed. Chem. 2012, 6, 107.(14) Fedosova, A. E.; Moshkovskiic, S. A.; Kuznetsovac, K. G.; Oliverab, B. M. Biochemistry-Moscow+Series B: Biomed. Chem. 2012, 6, 107.
15. [15]
  (15) Kolosov, A.; odchild, C. S.; Cooke, I. Pain Med. 2010, 11, 262. doi: 10.1111/pme.2010.11.issue-2(15) Kolosov, A.; odchild, C. S.; Cooke, I. Pain Med. 2010, 11, 262. doi: 10.1111/pme.2010.11.issue-2
16. [16]
  (16) Zhan, D. L;Wang, S.; Han,W.W.; Liu, J. S. Acta Chim. Sin. 2012, 70, 217. [詹冬玲, 王嵩, 韩葳葳, 刘景圣, 化学学报, 2012, 70, 217.] doi: 10.6023/A1108313(16) Zhan, D. L;Wang, S.; Han,W.W.; Liu, J. S. Acta Chim. Sin. 2012, 70, 217. [詹冬玲, 王嵩, 韩葳葳, 刘景圣, 化学学报, 2012, 70, 217.] doi: 10.6023/A1108313
17. [17]
  (17) Zhang, Q. Q.; Yao, Q. Z.; Zhang, S. P.; Bi, L. M.; Zhou, Z. G.; Zhang, J. Acta Phys. -Chim. Sin. 2014, 30, 371. [张青青, 姚其正, 张生平, 毕乐明, 周之光, 张骥. 物理化学学报, 2014, 30, 371.] doi: 10.3866/PKU.WHXB201312192(17) Zhang, Q. Q.; Yao, Q. Z.; Zhang, S. P.; Bi, L. M.; Zhou, Z. G.; Zhang, J. Acta Phys. -Chim. Sin. 2014, 30, 371. [张青青, 姚其正, 张生平, 毕乐明, 周之光, 张骥. 物理化学学报, 2014, 30, 371.] doi: 10.3866/PKU.WHXB201312192
18. [18]
  (18) Hou, T. J.; Xu, X. J. Curr. Pharm. Des. 2004, 10, 1011. doi: 10.2174/1381612043452721(18) Hou, T. J.; Xu, X. J. Curr. Pharm. Des. 2004, 10, 1011. doi: 10.2174/1381612043452721
19. [19]
  (19) Ding, J. J.; Ding, X. Q.; Zhao, L. F.; Chen, J. S. Prog. Chem. 2005, 17, 130. [丁俊杰, 丁晓琴, 赵立峰, 陈冀胜. 化学进展, 2005, 17, 130.](19) Ding, J. J.; Ding, X. Q.; Zhao, L. F.; Chen, J. S. Prog. Chem. 2005, 17, 130. [丁俊杰, 丁晓琴, 赵立峰, 陈冀胜. 化学进展, 2005, 17, 130.]
20. [20]
  (20) Audie, J.; Swanson, J. Chem. Biol. Drug. Des. 2013, 81, 50. doi: 10.1111/cbdd.2012.81.issue-1(20) Audie, J.; Swanson, J. Chem. Biol. Drug. Des. 2013, 81, 50. doi: 10.1111/cbdd.2012.81.issue-1
21. [21]
  (21) Hou, T. J.; Li, N.; Li, Y. Y.;Wang,W. J. Proteome Res. 2012, 11, 2982. doi: 10.1021/pr3000688(21) Hou, T. J.; Li, N.; Li, Y. Y.;Wang,W. J. Proteome Res. 2012, 11, 2982. doi: 10.1021/pr3000688
22. [22]
  (22) Hou, T. J.; Li, Y. Y.;Wang,W. Bioinformatics 2011, 27, 1814. doi: 10.1093/bioinformatics/btr294(22) Hou, T. J.; Li, Y. Y.;Wang,W. Bioinformatics 2011, 27, 1814. doi: 10.1093/bioinformatics/btr294
23. [23]
  (23) Hou, T. J.; Xu, Z.; Zhang,W.; McLaughlin,W. A.; Case, D. A.; Xu, Y.;Wang,W. Mol. Cell. Proteomics 2009, 8, 639. doi: 10.1074/mcp.M800450-MCP200(23) Hou, T. J.; Xu, Z.; Zhang,W.; McLaughlin,W. A.; Case, D. A.; Xu, Y.;Wang,W. Mol. Cell. Proteomics 2009, 8, 639. doi: 10.1074/mcp.M800450-MCP200
24. [24]
  (24) Ding, J. J.; Ding, X. Q.; Zhao, L. F.; Chen, J. S. Acta Pharm. Sin. 2005, 40, 340. [丁俊杰, 丁晓琴, 赵立峰, 陈冀胜. 药学学报, 2005, 40, 340.](24) Ding, J. J.; Ding, X. Q.; Zhao, L. F.; Chen, J. S. Acta Pharm. Sin. 2005, 40, 340. [丁俊杰, 丁晓琴, 赵立峰, 陈冀胜. 药学学报, 2005, 40, 340.]
25. [25]
  (25) Atkinson, R. A.; Kieffer, B.; Dejaegere, A.; Sirockin, F.; Lefevre, J. F. Biochemistry 2000, 39, 3908. doi: 10.1021/bi992651h(25) Atkinson, R. A.; Kieffer, B.; Dejaegere, A.; Sirockin, F.; Lefevre, J. F. Biochemistry 2000, 39, 3908. doi: 10.1021/bi992651h
26. [26]
  (26) Nielsen, K. J.; Adams, D.; Thomas, L.; Bond, T.; Alewood, P. F.; Craik, D. J.; Lewis, R. J. J. Mol. Biol. 1999, 289, 1405. doi: 10.1006/jmbi.1999.2817(26) Nielsen, K. J.; Adams, D.; Thomas, L.; Bond, T.; Alewood, P. F.; Craik, D. J.; Lewis, R. J. J. Mol. Biol. 1999, 289, 1405. doi: 10.1006/jmbi.1999.2817
27. [27]
  (27) Richard, J. L.; Katherine, J. N.; David, J. C.; Marion, L. L.; Denise, A. A.; Iain, A. S.; Tudor, L.; David, J. A.; Trudy, B.; Linda, T.; Aluu, J.; Jodi-Lea, M.; Roger, D.; Peter, R. A.; Paul, F. A. J. Biol. Chem. 2000, 275, 35335. doi: 10.1074/jbc.M002252200(27) Richard, J. L.; Katherine, J. N.; David, J. C.; Marion, L. L.; Denise, A. A.; Iain, A. S.; Tudor, L.; David, J. A.; Trudy, B.; Linda, T.; Aluu, J.; Jodi-Lea, M.; Roger, D.; Peter, R. A.; Paul, F. A. J. Biol. Chem. 2000, 275, 35335. doi: 10.1074/jbc.M002252200
28. [28]
  (28) Mason, J. S. Computer-Assisted Drug Design; Science Press: Beijing, 2007; p 307.(28) Mason, J. S. Computer-Assisted Drug Design; Science Press: Beijing, 2007; p 307.
29. [29]
  (29) Cerius 2 User Guide; Molecular Simulations Inc: San Die , 2000.(29) Cerius 2 User Guide; Molecular Simulations Inc: San Die , 2000.
30. [30]
  (30) Drwal, M. N.; Griffith, R. Drug Discovery Today: Technologies 2013, 10, e395.(30) Drwal, M. N.; Griffith, R. Drug Discovery Today: Technologies 2013, 10, e395.
31. [31]
  (31) Wilson, G. L.; Lill, M. A. Future Med. Chem. 2011, 3, 735. doi: 10.4155/fmc.11.18(31) Wilson, G. L.; Lill, M. A. Future Med. Chem. 2011, 3, 735. doi: 10.4155/fmc.11.18
32. [32]
  (32) G rge, P. M.; Ramachandran, J. Annu. Rev. Pharmacol. Toxicol. 1995, 35, 307. doi: 10.1146/annurev.pa.35.040195.001515(32) G rge, P. M.; Ramachandran, J. Annu. Rev. Pharmacol. Toxicol. 1995, 35, 307. doi: 10.1146/annurev.pa.35.040195.001515
33. [33]
  (33) Pallaghy, P. K.; Nielsen, K. J.; Craik, D. J.; Norton, R. S. Protein Sci. 1994, 3, 1833. doi: 10.1002/pro.v3:10(33) Pallaghy, P. K.; Nielsen, K. J.; Craik, D. J.; Norton, R. S. Protein Sci. 1994, 3, 1833. doi: 10.1002/pro.v3:10
34. [34]
  (34) Adams, D. J.; Berecki, G. Biochim. Biophys. Acta 2013, 1828, 1619. doi: 10.1016/j.bbamem.2013.01.019(34) Adams, D. J.; Berecki, G. Biochim. Biophys. Acta 2013, 1828, 1619. doi: 10.1016/j.bbamem.2013.01.019
35. [35]
  (35) Kazuki, S.; Cecile, R.; Nicole, M. M.; Toru, S.; Akira, O.; Atsuko, O.; Jae, I. K.; Toshiyuki, K.; Masami, T.; Michael, S. FEBS Lett. 1997, 414, 480. doi: 10.1016/S0014-5793(97)01056-9(35) Kazuki, S.; Cecile, R.; Nicole, M. M.; Toru, S.; Akira, O.; Atsuko, O.; Jae, I. K.; Toshiyuki, K.; Masami, T.; Michael, S. FEBS Lett. 1997, 414, 480. doi: 10.1016/S0014-5793(97)01056-9
36. [36]
  (36) Nielsen, K. J.; Adams, D. A.; Alewood, P. F.; Lewis, R. J.; Thomas, L.; Schroeder, T.; Craik, D. J. Biochemistry 1999, 38, 6741. doi: 10.1021/bi982980u(36) Nielsen, K. J.; Adams, D. A.; Alewood, P. F.; Lewis, R. J.; Thomas, L.; Schroeder, T.; Craik, D. J. Biochemistry 1999, 38, 6741. doi: 10.1021/bi982980u
37. [37]
  (37) Mould, J.; Yasuda, T.; Schroeder, C. I.; Beedle, A. M.; Doering, C. J.; Zamponi, G.W.; Adams, D. J.; Lewis, R. J. J. Biol. Chem. 2004, 279, 34705.(37) Mould, J.; Yasuda, T.; Schroeder, C. I.; Beedle, A. M.; Doering, C. J.; Zamponi, G.W.; Adams, D. J.; Lewis, R. J. J. Biol. Chem. 2004, 279, 34705.
38. [38]
  (38) Van Petegem, F.; Minor, D. L. Biochem. Soc. Trans. 2006, 34, 887. doi: 10.1042/BST0340887(38) Van Petegem, F.; Minor, D. L. Biochem. Soc. Trans. 2006, 34, 887. doi: 10.1042/BST0340887
39. [39]
  (39) Kajuti, S.; Cecile, R.; Nicole, M. M.; Toru. S.; Atsuko, O. FEBS Lett. 2000, 469, 147. doi: 10.1016/S0014-5793(00)01263-1(39) Kajuti, S.; Cecile, R.; Nicole, M. M.; Toru. S.; Atsuko, O. FEBS Lett. 2000, 469, 147. doi: 10.1016/S0014-5793(00)01263-1
40. [40]
  (40) Kazuki, S.; Cecile, R.; Nicole, M. M.; Toru, S.; Atsuko, O.; Kazushi, M.; Catherine, V. R.; Masami, T.; Michael, J. S. Biochem. Biophys. Res. Commun. 2000, 269, 254. doi: 10.1006/bbrc.2000.2284(40) Kazuki, S.; Cecile, R.; Nicole, M. M.; Toru, S.; Atsuko, O.; Kazushi, M.; Catherine, V. R.; Masami, T.; Michael, J. S. Biochem. Biophys. Res. Commun. 2000, 269, 254. doi: 10.1006/bbrc.2000.2284
41. [41]
  (41) Lew, M. J.; Flinn, J. P.; Pallaghy, P. K.; Murphy, R.; Whorlow, S. L.;Wright, C. E.; Norton, R. S.; Angus, J. A. J. Biol. Chem. 1997, 272, 12014. doi: 10.1074/jbc.272.18.12014(41) Lew, M. J.; Flinn, J. P.; Pallaghy, P. K.; Murphy, R.; Whorlow, S. L.;Wright, C. E.; Norton, R. S.; Angus, J. A. J. Biol. Chem. 1997, 272, 12014. doi: 10.1074/jbc.272.18.12014
42. [42]
  (42) Nadasdi, L.; Yamashiro, D.; Chung, D.; Tarczy-Hornoch, K.; Adriaenssens, P.; Ramachandran, J. Biochemistry 1995, 34, 8076. doi: 10.1021/bi00025a013
  (42) Nadasdi, L.; Yamashiro, D.; Chung, D.; Tarczy-Hornoch, K.; Adriaenssens, P.; Ramachandran, J. Biochemistry 1995, 34, 8076. doi: 10.1021/bi00025a013

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沈阳化工大学材料科学与工程学院沈阳 110142

ω-芋螺毒素的定量构效关系与虚拟筛选

English

Quantitative Structure-Activity Relationship and Virtual Screening of ω-Conotoxins

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通讯作者: 陈斌, bchen63@163.com

中国化学会秘书处

ω-芋螺毒素的定量构效关系与虚拟筛选

English

Quantitative Structure-Activity Relationship and Virtual Screening of ω-Conotoxins

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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