摘要
定量构效关系(QSAR)研究是农药分子设计中很重要的方法,本文详细介绍了2D-QSAR中的Hansch-Fujita方法及3D-QSAR中的比较分子场分析(CoMFA)方法和比较分子相似指数分析(CoMSIA)方法,并对Hansch-Fujita方法中使用的各种类型的参数进行了比较分析。并基于上述三种方法,开展了两方面的研究。
为了更全面地揭示2-芳基苯并二氢吡喃-4-酮类衍生物的抗菌活性与其结构之间的关系,在本课题组前期进行的Hanseh-Fujita QSAR分析的基础上,采用CoMFA、CoMSIA等3D-QSAR分析方法对其三维结构活性关系进行了探讨。与Hansch-Fujita QSAR分析的比较、组合加深了对该系列化合物的结构活性关系的理解,有助于构建配体与假想受体的连接模式。该连接模式无疑为进一步设计新型的抗菌试剂提供了很好的指导。
磺酰脲类除草剂的开发,一直是当前除草剂化学中一个重要的研究领域,一方面,科学家们基于磺酰脲类化合物的结构特征,提出了数种受体作用模型;另一方面,针对该类抑制剂的靶标(Acetohydroxyacid synthase [AHAS],EC2.2.1.6),构建了分子模型和对接模型。若能把抑制剂的构效关系与酶结合位点的性质联系起来研究,可能会得到更多有关除草剂抑制机理的信息。为此,鉴于Duggleby课题组最近报道的磺酰脲化合物和酵母AHAS复合物的晶体结构,本研究从氯嘧磺隆与AHAS酶催化亚基复合物晶体中提取氯嘧磺隆的构象为初始构象,构建了一系列磺酰脲类化合物。在DFT方法下,采用B3LYP函数对构建的结构进行了优化,并计算了基于静电势拟合的电荷。利用DFT方法计算的量子化学参数进行了Hansch-Fujita QSAR分析,同时采用CoMFA和CoMSIA等方法对磺酰脲类化合物的结构活性关系进行了探讨。得到的QSAR模型进一步验证了复合物中磺酰脲化合物与酶的连接模式,并为下一步的虚拟筛选提供了一个非常有用的工具。
Quantitative structure-activity relationship (QSAR) studies are important approaches in the design of pesticidal molecules; the method of Hansch-Fujita QSAR of 2D-QSAR, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) are been introduced in detail in this paper, and the different types of descriptors of Hansch-Fujita QSAR are been compared and discussed. Based on three methods above, two kinds of studies are been carried out.To further explore the comprehensive structure-activity relationship of the antifungal 2-Aryl-4- chromanones, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), are performed to explore the structure-activity relationship of the antifungal 2-Aryl-4- chromanones, based on the result of the Hansch-Fujita QSAR analysis that was performed in our group previously. The compare and the combination with the result of the Hansch-Fujita QSAR analysis provide more comprehensive understand about the relationship between the structure and the activity, and help to construct the binding model between the ligand and the plausible receptor. The binding model provides a helpful guideline for further designing novel potent antifungal agents definitely.The development of sulfoylurea herbicides has always been the important study field in herbicide chemistry nowadays; on one hand, several kinds of receptor action models have been advanced by scientists, based on the character of the structure of sulfonylureas; on the other hand, molecular models and docking models have been constructed according to the information of their target (Acetohydroxyacid synthase [AHAS], EC2.2.1.6). More information about the inhibition mechanism would be gotten if the study is based on the connection of SAR of inhibitors and the property of the binding site of enzyme. For that, according to the crystal structure of yeast AHAS in complex with sulfonylureas that were reported by the group of Duggleby,
the geometry of chlorimuron in the crystal structure of yeast AHAS in complex with chlorimuron is extracted as initial structure in this study, which is used to construct a series of sulfonylurea herbicides molecules. All of the constructed structures are fully optimized by using the DFT method with the B3LYP functional, and electrostatic potential (ESP)-fitting charges are derived from the DFT calculation. Then, DFT-based quantum chemical descriptors are used to carry out Hansch-Fujita QSAR analysis, and at the same time, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), are performed to explore the structure-activity relationship of sulfonylurea compounds. The derived QSAR models further validate the binding model of sulfonylurea compounds and AHAS, and provide a very useful tool in the next virtual screening.
引文
1.仇缀百.药物设计学.第一版.北京:高等教育出版社,1999.196～208
2. Mati. Karelson, Victor S. Chem. Rev. 1996,96:1027～1043.
3. Wolff M. E. Berger's Medieinial Chemistry and Drug Discovery. 5th. Ed. Vol. 1. Principles and Practice. New York: John Wiley&Sons, 1995.497～572.
4. Kubinyi H. QSAR: Hansch Analssis and Related Approches. Vol. 1. Methods and Principles in Medicinal Chemistry. Weinheim: VCH, 1993.1～51
5.徐文芳.新药设计原理与方法.北京:中国医药科技出版社,1997.170～189
6. Swein C. G,Lupton E. C. Jr. J. AM. Chem. Soc., 1968, 90:4328
7. Taft R. W. Jr. In: Newman M S, ed. Steric Effects in Organic Chemistry. New York: Wily, 1956
8. Daniel C., Wood F. S. Fitting Equations to Data. New York: Wily, 1980
9. Draper N. R., Smith H. Applied Regression Analysis, 2nd Edition. New York: Wily, 1981
10. Cocchi M., Menziani M. C., De. Benedetti., P. G., Cruciani, G. Chemom. Intell. Lab.Sys. 1992,14:209
11. Diercksen, G. H. E, Wilson, S. Methods in Computational Molecular Physics. Eds. D. Reidel Publ. Co.: Dordreeht, 1983
12. Moller C., Plesset M. S. Phys. Chem. 1989, 93:1697
13. Gauss J., Cremer D. Adv. Quantum. Chem. 1992. 23:205
14. Franke R. Theoretical Drug Design Methods. Elsevier: Amsterdam, 1984. 115～123
15. Becke A. D. Phys. Rev. A 1988.38:3098～3100
16. Lee C., Yang W., Parr R. G. Phys. Rev. B 1988.37:785～789
17. (a) Becke A. D. J. Chem. Phys. 1993.98:1372～1377 (b) Becke A. D. J. Chem. Phys. 1993.98:5648～5652
18. (a) Hirata, S., Zhan, C.-G., Apra, E., Windus, T. L., Dixon D. A. J. Phys. Chem. A 2003, 107: 10154～10158. (b) Zhan, C.-G., Dixon D.A. J. Phys. Chem. B 2002. 106:10311～10325 (c) Zhan, C.-G., Dixon D. A., Matsuzawa, N. N., Ishitani A., Uda T. J. Fluorine Chem. 2003. 122:27～35 (d) Zhan, C.-G., Nichols J. A., Dixon D. A. J. Phys. Chem. A 2003. 107:4184～4195. (e) Zhan, C.-G., Dixon D. A. J. Mol. Spectrosc. 2002.216:81～89
19. Perdew J. e., Wang Y. Phys. ReV. B 1992.45:13244～13249
20. Foresman J. B., Frisch A. Exploring chemistry with electronic structure methods. Gaussian Inc.: Pittsburgh, PA, 1996
21. Sulpizi M., Folkers G., Rothlisberger U., Carloni P., Scapozza L. 2002. 21: 173～181
22. Bernardi F., Bottoni A., Garavelli M. Quant. Struct.-Act. Relat. 2002. 21: 128～148
23. Arulmozhiraja S., Morita M. Chem. Res. Toxicol. 2004. 17:348～356
24. Kubinyi H. 3D-QSARin drug Design: Theoretical Methods and Application. Leiden: ESCOM, 1993
25.王红武,陈凯先.三维定量构效关系的研究与应用.国外医学(药学分册),1993.20:325
26. Hopfinger A. J. J. AM. Chem. Soc, 1980.102(8):7196
27. Hopfinger A. J. Arch Biochem Biophy. 1981.206(1):153
28. Cripper G. M. Distance Geometry and Conformational Calculations. In: Baldwin D, ed. Chemometric Research Studies. Chichester: Wiley, 1987.1
29. Ghose A U., J. Med. Chem. 1984.27(7):901
30. Cramer R. D. Ⅲ, Patterson D. E., Bunce J. D. J. Am. Chem. Soc. 1988. 110:5959～5967
31. Klebe G., Abraham U., Mietzner T. J. Med. Chem. 1994.37:4130～4146
32. Klebe G., Abraham U. J. Comput.-Aided Mol. Des. 1999.13:1～10
33. Wold S., Rhue, A., Wold H., Dunn W.J. I. SIAMJ. Sci. Stat. Comput. 1984. 5:735～743
34. Wold S., Albano C., Dunn W. J. Ⅲ., Edlund U., Esbensen K., Geladi P., Hellberg S., Johanson E., Lindberg W., Sjostrom M. NATO ASISer., Ser. C 1984. 138: 17～95
35. Clark M., Cramer R. D. Ⅲ. Quant. Struct.-Act. Relat. 1993. 12:137～145
36. Bush B. L., Nachbar R. B. J. Comput.-Aided Mol. Des. 1993.7:587～619
37. Wermuch C G. Trends in QSAR and Molecular Modelling 92. Leiden: ESCOM, 1993
38. Kubinyi H. 3D-QSAR in Drug Design: Theoretical Methods and applications. Leiden: ESCOM, 1993
39. Padmavati, M., Reddy, Arjula R. The Second International Electronic Conference on Synthetic Organic Chemistry (ECSOC-2). 1998. Sept 1-30
40. Arnoldi, A., Carughi, M., Farina, G., Merlini. L., Parrino, M. G. J. Agric. Food Chem. 1989.37:508-512
41. Arnoldi, A., Farina, G., Galli, R., Merlini, L., Parrino, M. G. J. Agric. Food Chem. 1986.34:185-188
42. Weidenborner, M., Jha. H. C. Pestic. Sci. 1993.38:347-351
43. Weidenborner, M., Jha. H. C. Mycol. Res. 1997.101:733-736
44. Aida, Y., Tamogami, S., Kodama, O., Tsukiboshi, T. Biosci. Biotechnol. Biochem. 1996.60:1495～1496
45. Arnoldi, A., Merlini, L. J. Agric. Food Chem. 1990. 38:834～838
46. Carter, G. A., Chamberlain, K., Wain, R. L. Ann. Appl. Biol. 1978.19:107～124
47. Adesanya, S. A., O' Neill, M. J., Roberts, M. F.Physiol. Mol. Plant Pathol. 1986,29:95～103
48. Laks, P. E., Pruner, R.S. Phytochemistry. 1989.28:87～91
49. Kodama, 0., Miyakawa, J., Tadami, T., Kiyosawa, S. Phytochemistry 1992. 31:3807～3809
50. Ding, Y., Yang, G. F. Chinese J. Appl. Chem. 2001.18:785～788
51. Yang, G. F., Jiang, X. H., Ding, Y., Yang, H. Z. Chinese J. Chem. 2001.19: 423～428
52. Boulamwini, J. K., Assefa, H. J. Med. Chem. 2002.45:841～852
53.杨华铮.农药分子设计.第一版.北京:科学出版社,2003.285
54.牛聪伟.具有重要农学意义的乙酰羟基酸合成酶的化学生物学研究:[博士学位论文].天津:南开大学元素有机化学研究所,2005
55. Jennifer A. McCourt, Siew Siew Pang, Luke W. Guddat. Biochem. 2005.44:2330～2338
56. Siew Siew Pang, Luke W., Guddat. J. Bio. Chem. 2003.278:7639～7644