B-Raf激酶在促分裂素原活化蛋白激酶(MAPK)信号转导通路中起着重要作用,已被确定为癌症治疗非常有吸引力的靶标.新型高效B-Raf抑制剂的开发成为癌症治疗的一个热门研究领域.本文以结构多样的B-Raf II型抑制剂为研究对象,联合应用分子对接和定量构效关系(QSAR)模型研究其定量构效关系去探讨抑制活性的起源.两个主题作为研究重点:生物活性构象和描述符.首先对分子对接方法(Glide、Gold、LigandFit、Cdocker和Libdock)进行准确性评价,后将研究的对象分子对接到B-Raf活性位点并获得生物活性构象.基于准确的对接结果,计算得到16个打分评价函数和21个能量描述符,以此构建定量构效关系模型. QSAR结果表明模型具有高度精确的拟合和强的预测能力(模型M1: r2 = 0.852, r(CV)2 = 0.790, rpre2 = 0.864;模型M2: r2 = 0.738, r(CV)2 = 0.812, rpre2 = 0.8605).同时探讨了对抑制活性有重要影响的描述符,结果表明打分评价函数(G_Score, -ECD, Dock_Score, PMF)与能量描述符(S(hb_ext), DE(int), Emodel)对抑制活性影响非常大.通过虚拟筛选和QSAR模型理论预测,一些新的具有潜在抑制活性的化合物作为B-Raf II型抑制剂被获得.上述信息对于进一步设计新颖高效的B-Raf II型抑制剂提供了有用的指导. B-Raf kinase plays an important role in the mitogen-activated protein kinase (MAPK) signaling transmission pathway and has been identified as an attractive target for cancer therapy. The exploitation of novel and efficient B-Raf inhibitors has become a hot research topic. In this study, we investigated quantitative structure-activity relationship (QSAR) to probe the origins of the inhibitory activities of B-Raf Type II inhibitors. We used structurally diverse B-Raf Type II inhibitors and an integrated docking and QSAR extended method. We focused mainly on two themes: bioactive conformations and descriptors. First, various molecular docking methods (Glide, Gold, LigandFit, Cdocker, and Libdock) were evaluated, and then all molecules were docked into the B-Raf active site to obtain the bioactive conformations. Secondly, based on the docking results, 16 scoring functions and 21 docking-generated energy-based descriptors were calculated to construct regression models. The results gave highly accurate fitting and had strong predictive abilities (M1: r2 = 0.852, r(CV)2 = 0.790, rpre2 = 0.864; M2: r2 = 0.738, r(CV)2 = 0.812, rpre2 = 0.8605). The important descriptors were also explored to elucidate the main factors influencing the inhibition activities. The models suggested that the scoring functions (G_Score, -ECD, Dock_Score, and PMF) and docking-generated energy-based descriptors (S(hb_ext), DE(int), and Emodel) were significant. Some new compounds that are potential B-Raf inhibitors were obtained through virtual screening and theoretical predictions using the established models. Such information is useful in guiding the design of novel and robust B-Raf Type II inhibitors
4 Samowitz W. S. ; Sweeney C. ; Herrick J. ; Albertsen H. ; Levin T. R. ; Murtaugh M. A. ; Wolff R. K. ; Slattery M. L. Cancer Res 2005, 65, 6063. doi: 10.1158/0008-5472.CAN-05-0404
[3]
6 Wang X. ; Kim J. J. Med. Chem 2012, 55 (17), 7332. doi: 10.1021/jm300613w
[4]
9 Wilhelm S. M. ; Dumas J. ; Adnane L. ; Lynch M. ; Carter C. A. ; Schütz G. ; Thierauch K. H. ; Zopf D. Int. J. Cancer 2011, 129 (1), 245. doi: 10.1002/ijc.v129.1
[5]
15 Holderfield M. ; Deuker M. M. ; McCormick F. ; McMahon M. Nat. Rev. Cancer 2014, 14, 455. doi: 10.1038/nrc3760
[6]
35 Roy K. Expert Opin. Drug Discov 2007, 2, 1567. doi: 10.1517/edc.2007.2.issue-12
[7]
37 Tropsha A. ; Gramatica P. ; Gombar V. K. QSAR Comb. Sci 2003, 22, 69.
[8]
17 Hartsough E. ; Shao Y. ; Aplin A. E. J. Invest. Dermatol 2014, 134, 319. doi: 10.1038/jid.2013.358
[9]
19 Zhang F. ; Lu T. ; Tang W. F. Prog. Pharm. Sci 2014, 38, 31.
[10]
20 Enyedy I. J. ; Egan W. J. J. Comput. Aided Mol. Des 2008, 22, 161. doi: 10.1007/s10822-007-9165-4
[11]
22 Lin J. ; Li Z. G. ; Zou J. W. ; Lu S. Y. Acta Chim. Sin 2012, 11, 1309.
[12]
23 Li X. D. ; Hou T. J. ; Xu X. J. Acta Phys. -Chim. Sin 2005, 21, 504. doi: 10.3866/PKU.WHXB20050509[
24 Li M. Y. ; Xia L. Journal of China Pharmaceutical University 2003, 34 (6), 586.
[15]
李敏勇; 夏霖. 中国药科大学学报, 2003, 34 (6), 586.
[16]
26 Maestro, Version 9.0; Schr？ dinger, L. L. C.: New York, 2011
[17]
28 Discovery Studio Client, Version 2.5; Accelrys Inc.: San Diego, 2008
[18]
30 Fr？czek T. ; Siwek A. ; Paneth P. J. Chem. Inf. Model 2013, 53, 3326. doi: 10.1021/ci400427a
[19]
36 Qin L. T. ; Liu S. S. ; Xiao Q. F. ; Wu Q. S. Environ. Chem 2013, 32, 1205.
[20]
2 Davies H. ; Bignell G. R. ; Cox C. ; Stephens P. ; Edkins S. ; Clegg S. ; Teague J. ; Woffendin H. ; Garnett M. J. ; Bottomley W. ; Davis N. ; Dicks E. ; Ewing R. ; Floyd Y. ; Gray K. ; Hall S. ; Hawes R. ; Hughes J. ; Kosmidou V. ; Menzies A. ; Mould C. ; Parker A. ; Stevens C. ; Watt S. ; Hooper S. ; Wilson R. ; Jayatilake H. ; Gusterson B. A. ; Cooper C. ; Shipley J. ; Hargrave D. ; Pritchard-Jones K. ; Maitland N. ; Chenevix-Trench G. ; Riggins G. J. ; Bigner D. D. ; Palmieri G. ; Cossu A. ; Flanagan A. ; Nicholson A. ; Ho J. W. C. ; Leung S. Y. ; Yuen S. T. ; Weber B. L. ; Seigler H. F. ; Darrow T. L. ; Paterson H. ; Marais R. ; Marshall C. J. ; Wooster R. ; Stratton M. R. ; Futreal P. A. Nature 2002, 417, 949. doi: 10.1038/nature00766
[21]
3 Wan P. T. ; Garnett M. J. ; Roe S. M. ; Lee S. ; Niculescu-Duvaz D. ; Good V. M. ; Jones C. M. ; Marshall C. J. ; Springer C. J. ; Barford D. ; Marais R. Cell 2004, 116, 855. doi: 10.1016/S0092-8674(04)00215-6
[22]
5 Riesco-Eizaguirre G. ; Gutiérrez-Martínez P. ; García-Cabezas M. A. ; Nistal M. ; Santisteban P. Endocr-Relat. Cancer 2006, 13, 257. doi: 10.1677/erc.1.01119
[23]
10 Strumberg D. ; Schultheis B. Expert Opin. Investig. Drugs 2012, 21 (6), 879. doi: 10.1517/13543784.2012.684752
[24]
11 Chapman P. B. ; Hauschild A. ; Robert C. ; Haanen J. B. ; Ascierto P. ; Larkin J. ; Dummer R. ; Garbe C. ; Testori A. ; Maio M. ; Hogg D. ; Lorigan P. ; Lebbe C. ; Jouary T. ; Schadendorf D. ; Ribas A. ; O'Day S. J. ; Sosman J. A. ; Kirkwood J. M. ; Eggermont A. M. M. ; Dreno B. ; Nolop K. ; Li J. ; Nelson B. ; Hou J. ; Lee R. J. ; Flaherty K. T. ; McArthur G. A. N. Engl. J. Med 2011, 364, 2507. doi: 10.1056/NEJMoa1103782
[25]
7 Wilhelm S. M. ; Carter C. ; Tang L. ; Wilkie D. ; McNabola A. ; Rong H. ; Chen C. ; Zhang X. ; Vincent P. ; McHugh M. ; Cao Y. ; Shujath J. ; Gawlak S. ; Eveleigh D. ; Rowley B. ; Liu L. ; Adnane L. ; Lynch M. ; Auclair D. ; Taylor I. ; Gedrich R. ; Voznesensky A. ; Riedl B. ; Post L. E. ; Bollag G. ; Trail P. A. Cancer Res 2004, 64, 7099. doi: 10.1158/0008-5472.CAN-04-1443
[26]
8 Wilhelm S. ; Carter C. ; Lynch M. ; Lowinger T. ; Dumas J. ; Smith R. A. ; Schwartz B. ; Simantov R. ; Kelley S. Nat. Rev. Drug Discov 2006, 5 (10), 835. doi: 10.1038/nrd2130
[27]
12 Bollag G. ; Tsai J. ; Zhang J. ; Zhang C. ; Ibrahim P. ; Nolop K. ; Hirth P. Nature. Rev. Drug. Discov 2012, 11, 873. doi: 10.1038/nrd3847
[28]
13 Rheault T. R. ; Stellwagen J. C. ; Adjabeng G. M. ; Hornberger K. R. ; Petro K. G. ; Waterson A. G. ; Dickerson S. H. ; Mook R. A. Jr. ; Laquerre S. G. ; King A. J. ; Rossanese O. W. ; Arnone M. R. ; Smitheman K. N. ; Kane-Carson L. S. ; Han C. ; Moorthy G. S. ; Moss K. G. ; Uehling D. E. ACS Med. Chem. Lett 2013, 4, 358. doi: 10.1021/ml4000063
[29]
14 Kim D. H. ; Sim T. Arch. Pharm. Res 2012, 35, 605. doi: 10.1007/s12272-012-0403-5
[30]
16 Ackerman A. ; Klein O. ; McDermott D. F. ; Wang W. ; Ibrahim N. ; Lawrence D. P. ; Gunturi A. ; Flaherty K. T. ; Hodi F. S. ; Kefford R. ; Menzies A. M. ; Atkins M. B. ; Long G. V. ; Sullivan R. J. Cancer 2014, 120, 1695. doi: 10.1002/cncr.28620
[31]
18 Bucheit A. D. ; Davies M. A. Biochem. Pharmacol 2014, 87 (3), 381. doi: 10.1016/j.bcp.2013.11.013
[32]
张帆; 陆涛; 唐伟方. 药学进展, 2014, 38, 31.
[33]
21 Kroemer R. T. Curr. Protein Pept. Sci 2007, 8, 312. doi: 10.2174/138920307781369382
[34]
林军; 李祖光; 邹建卫; 陆绍永. 化学学报, 2012, 11, 1309.
[35]
25 Patel H. M. ; Noolvi M. N. ; Sharma P. ; Jaiswal V. ; Bansal S. ; Lohan S. ; Kumar S. S. ; Abbot V. ; Dhiman S. ; Bhardwaj V. Med. Chem. Res 2014, 23, 4991. doi: 10.1007/s00044-014-1072-3
[36]
27 GOLD, Version 4.0; Astex Technology: Cambridge, 2001
[37]
29 Chen L. ; Chen X. J. Mol. Graph. Model 2012, 33, 35. doi: 10.1016/j.jmgm.2011.11.003
[38]
31 SYBYL, Version 7.1; Tripos Inc.: St. Louis, Missouri, 63144, U. S. A.
[39]
32 Hassan M. ; Bielawski J. ; Hempel J. ; Waldman M. Mol. Divers 1996, 2 (1-2), 64. doi: 10.1007/BF01718702
[40]
33 Matter H. ; Potter T. J. Chem. Inf. Comput. Sci 1999, 39 (6), 1211. doi: 10.1021/ci980185h
[41]
34 TSAR Software, Version 3. 3; Accelrys Inc.: Oxford, England
