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分子动力学模拟技术

分子动力学模拟技术. 汇报人：翟丽娟 导师：薛照辉 副教授 2012.11.13. Contents. 分子模拟背景简介. 分子对接技术的应用情况. 文献举例. 软件的操作示范. 分子模拟背景简介. 分子模拟. 化学. 医学. 物理. 材料学. 生命科学. 分子模拟背景简介. 分子对接技术应用情况. 分子对接就是从已知结构的受体（靶蛋白或活性位点）和配体出发，通过化学计量学方法模拟分子的几何结构和分子间作用力来进行分子间相互作用识别并预测受体 - 配体复合物结构的方法。

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分子动力学模拟技术

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  1. 分子动力学模拟技术 汇报人：翟丽娟 导师：薛照辉副教授 2012.11.13

  2. Contents 分子模拟背景简介 分子对接技术的应用情况 文献举例 软件的操作示范

  3. 分子模拟背景简介 分子模拟 化学 医学 物理 材料学 生命科学

  4. 分子模拟背景简介

  5. 分子对接技术应用情况 • 分子对接就是从已知结构的受体（靶蛋白或活性位点）和配体出发，通过化学计量学方法模拟分子的几何结构和分子间作用力来进行分子间相互作用识别并预测受体-配体复合物结构的方法。 • 目前，分子对接技术主要在药物研究领域发挥了重要作用。例如，研究小分子探针与细胞内生物大分子的相互作用，寻找小分子在生物体内的作用靶点，为新药开发寻找突破口；以结构生物学为基础，对正常生理过程中及与肝癌、肝炎等疾病相关的重要蛋白质的结构和功能进行系统的研究与分析，得到蛋白质药靶的三维结构，进行药物与靶标蛋白相互作用的动力学模拟研究。 • 早期的药物设计偏重于提高小分子活性的设计，并取得了一定的成果。因此，发展、利用各种分子对接方法进行新药的发现将成为一个研究热点。

  6. 文献 Synthesis, biological evaluation and molecular docking studies of amide-coupled benzoic nitrogen mustard derivatives as potential antitumor agents From: Bioorganic & Medicinal Chemistry Authors: Qing-Zhong Zheng, Fei Zhang, Kui Cheng, YingYang, YuChen, YongQian, Hong-Juan Zhang, Huan-Qiu Li, Chang-Fang Zhou, Shu-Qing An *, Qing-Cai Jiao *, Hai-Liang Zhu *

  7. 文献 I Introduction II Experiment Contents III Results and discussion IV Conclusion

  8. 文献-Introduction Breast cancer EGFR Ovarian cancer Receptor protein tyrosine kinases Lung cancer HER-2 Prostate cancer

  9. 文献-Introduction Nitrogen mustards are widely used in the treatment of a variety of cancer. But because of the high reactivity of nitrogen mustards, they are chemically unstable and produce many unwanted side effects including bone marrow toxicity and genotoxicity. However, benzoic nitrogen mustard possessing relatively low toxicity is one of the earliest antitumor drugs in antibody-directed enzyme prodrug therapy. It is reported that benzoic nitrogen mustard derivatives possess favorable anticancer activity. • The synthesis • Biological evaluation • Docking stimulation

  10. 文献-Experiment • General procedure for • the preparation of • target compounds 5a–t • Preparation, purification of HER-2 and EGFR and inhibitory assay ELISA assay Experiment • Cell proliferation assay • Molecular docking modeling MTT assay

  11. 文献-Result and discussion

  12. 文献-Result and discussion

  13. 文献-Result and discussion

  14. 文献-Conclusion Conclusion • A series of new amide-coupled benzoic nitrogen mustard derivatives were synthesized, some of which displayed potent EGFR and HER-2 inhibitory. • Of all the studied compounds, compounds 5b and 5t exhibited the most potent inhibitory activity (as for 5b, IC50= 0.08μM for EGFR and IC50= 0.41μM for HER-2; as for 5t, IC50= 0.09μM for EGFR and IC50= 0.35μM for HER-2). • Docking simulation was performed to position compounds 5b and 5t into the EGFR active site to determine the probable binding model. • Antiproliferative assay results indicated that some of the benzoic nitrogen mustard derivatives possessed high antiproliferative activity against MCF-7. In particular, compounds 5b and 5t with potent inhibitory activity in tumor growth inhibition would be potential antitumor agents.

  15. 文献-Reference 1. Yarden, Y.; Sliwkowski, M. X. Mol. Cell Biol. 2001, 2, 127. 2. Hynes, N. E.; Stern, D. F. Biochim. Biophys. Acta 1994, 1198, 165. 3. Slamon, D. J.; Clark, G. M.; Wong, S. G.; Levin, W. J.; Ullrich, A.; McGuire, W. L.Science 1987, 235, 177. 4. Slamon, D. J.; Godolphin, W.; Jones, L. A. Science (Wash. DC) 1989, 244, 707 5. Scheurle, D.; Jahanzeb, M.; Aronsohn, R. S.; Watzek, L.; Narayanan, R. H. Anticancer Res. 2000, 20, 2091. 6. Cox, G.; Vyberg, M.; Melgaard, B.; Askaa, J.; Oster, A.; O’Byrne, K. J. Int. J. Cancer 2001, 92, 480. 7. Gullick, W. J. Br. Med. Bull. 1991, 47, 87. 8. Moscatello, D. K.; Holgado-Mudruga, M.; Godwin, A. K.; Ramirez, G.; Gunn, G.; Zoltick, P. W.; Biegel, J. A.; Hayes, R. L.; Wong, A. J. Cancer Res. 1995, 55, 5536. 9. Wikstrand, C. J.; McLendon, R. E.; Friedman, A.; Bigner, D. D. Cancer Res. 1997, 57, 4130.

  16. 文献-Reference 10. Bridges, A. J. Curr. Med. Chem. 1999, 6, 825. 11. Boschelli, D. H. Drugs Future 1999, 24, 515. 12. Denny, W. A. Curr. Med. Chem. 2001, 8, 533. 13. Alexanian, R.; Dimopoulos, M. A. N. Eng. J. Med. 1994, 330, 484. 14. Hansson, J.; Lewensohn, R.; Ringborg, U.; Nilsson, B. Cancer Res. 1987, 47, 2631. 15. Rodney, M.; Carney, J. P.; Kelley, M. R.; Glassner, B. J.; Williams, D. A.; Samson, L. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 206. 16. Brendal, M.; Ruhland, A. Mutat. Res. 1984, 133, 51. 17. Zakaria, R.; Fouad, B.; Qiyu, Q.; Christopher, W.; Janet, M. H.; John, A. H.; Bertrand, J. J. C. J. Med. Chem. 2007, 50, 2605. 18. Springer, C. J.; Antoniw, P.; Bagshawe, K. D.; Searle, F.; Bisset, G. M.; Jarman, M. J. Med. Chem. 1990, 33, 677. 19. Niculescu-Duvaz, I.; Scanlon, I.; Niculescu-Duvaz, D.; Friedlos, F.; Martin, J.; Marais, R.; Springer, C. J. J. Med. Chem. 2004, 47, 2651. 20. Taylor, C. K.; Abel, P. W.; Hulce, M.; Smith, D. D. Chem. Biol. Drug Des. 2007, 70, 216.

  17. Gromacs407 软件的示范操作 VMD Autodock

  18. 计划： 学习 • 继续学习一下软件的操作 实验 • 学习液相等一些分析技术 • 跟师兄师姐一起做体外细胞实验 文章 • 读文章，为以后实验做积累 • 将文章写完，试着投一投

  19. Thank you^-^~~

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