原癌蛋白PIM-1激酶抑制剂的分子模拟研究
|
摘要
小分子蛋白激酶抑制剂的开发是靶向抗癌研究的热点之一,分子模拟技术已被广泛应用于小分子蛋白激酶抑制剂的设计和发现。原癌蛋白(protooncogene)PIM(Provirus Integration site for Moloney murine leukemia virus)激酶在细胞生存、增殖、分化和凋亡以及肿瘤发生和发展过程中有重要作用。PIM-1激酶过表达能够促进细胞周期进程并抑制细胞凋亡,抑制PIM-1激酶已被证实能够抑制癌细胞的生长,因此PIM-1激酶被认为是开发抗癌药物的潜在靶标。
本论文工作以PIM-1激酶抑制剂为研究对象,采用分子模拟(包括分子对接、分子动力学、结合自由能计算和三维定量构效关系等方法)研究其与PIM-1激酶的相互作用机理以及计算或预测其抑制活性,以期为设计新型、高效的PIM-1激酶抑制剂和先导化合物虚拟筛选提供理论基础和资料参考。全文共分七章：
1介绍本论文的研究背景、研究方法及研究内容。
2综述PIM-1激酶抑制剂的研究进展。
3研究PIM-1激酶残基柔性对抑制剂结合模式预测的影响。首先通过对15个PIM-1激酶抑制剂复合物进行复原对接,确定Goldscore是最适合于抑制剂结合模式预测的打分函数。然后通过交叉对接及晶体结构比较分析,确定PIM-1激酶G-loop的柔性以及Phe49、Lys67和Glu89的侧链取向影响抑制剂结合模式的预测。
4预测先导抑制剂SMI-4a的结合模式。首先采用分子对接预测先导抑制剂的结合模式,然后对获得的两种结合模式的抑制剂—PIM-1激酶复合物结构进行分子动力学模拟,最后采用分子力学—泊松—波尔兹曼表面积(]molecular mechanics-Poisson-Boltzmann surface area, MM-PBSA)方法计算并比较两种结合模式的结合自由能,推测了先导抑制剂SMI-4a的结合模式。
5研究异恶唑喹啉二酮类PIM-1激酶抑制剂的作用机理,并进行新化合物设计。首先采用分子对接获得抑制剂的结合模式,并分析对接打分与结合亲和力的相关性。然后对获得的抑制剂——PIM-1激酶复合物进行分子动力学模拟,采用线性相互作用能(Linear interaction energy, LIE)方法计算抑制剂与PIM-1激酶的相互作用能,建立LIE模型用于结合亲和力计算,并分析了LIE方法计算结合亲和力的准确性。最后基于先导抑制剂的结合模式及其抑制活性,提出了异恶唑喹啉二酮类化合物可能的优化位置,并设计了3个新的化合物进行验证。
6分析线性响应—分子力学—泊松—波尔兹曼表面积(linear response-MM-PBSA approach, LR-MM-PBSA)方法预测苯并噻吩嘧啶酮类PIM-1激酶抑制剂结合亲和力的可行性与准确性。首先采用分子对接预测该类抑制剂的结合模式,并分析对接打分与结合亲和力的相关性。然后优化复合物结构,并采用MM-PBSA计算相互作用能。用训练集建立3参数LR-MM-PBSA模型,并用于预测其余化合物的结合亲和力。
7分子对接结合三维定量构效关系(Three Dimensional Quantitative Structure-Activity Relationship,3D QSAR)研究三唑并毗啶类化合物对PIM-1激酶的抑制机理。采用分子对接获得该类抑制剂的活性构象,并基于对接构象建立比较分子力场分析(Comparative Molecular Field Analysis, CoMFA)和比较分子相似性指数分析(Comparative Molecular Similarity Index Analysis, CoMSIA)模型,得到的模型可以成功预测该类化合物的活性。同时将CoMFA和CoMSIA三维等势面图与活性位点叠合,分析了该类化合物的抑制机理。
Targeted inhibition of protein kinases has become an attractive therapeutic strategy in the treatment of cancer. Molecular simulation techniques have been widely applied to design and discovery of small molecule protein kinase inhibitors. Protooncogene PIM (Provirus Integration site for Moloney murine leukemia virus) kinases have been shown to have diverse biological roles in cell survival, proliferation, differentiation and apoptosis, as well as play an important role in tumor occurrence and development. Overexpression of the PIM-1kinase has been found that can promote cell cycle progression and inhibit apoptosis of cells. It has been confirmed that inhibition of cancer cells growth by inhibition of the PIM-1kinase, so the PIM-1kinase has been widely considered as attractive target for the development of anticancer drugs.
In this thesis, in order to provide theoretical foundation and reference for designing novel and potent inhibitors of the PIM-1kinase and virtual screening for lead discovery, the inhibition mechanism of some PIM-1kinase inhibitors were studied as well as inhibitor activity were calculated and predicted by molecular modeling, including molecular docking, molecular dynamics and binding free energy calculations, and three-dimensional quantitative structure-activity relationship (3D QSAR). The thesis included seven chapters and presented as follows:
Chapter1The research background, methodology and content of this thesis were introduced.
Chapter2The research progress of PIM-1kinase inhibitors in experimental and theoretical calculation was summarized.
Chapter3The effect of the residues flexibility of PIM-1kinase on the inhibitor binding mode prediction was studied. Firstly, through self-docking of15PIM-1kinase inhibitor complexs, Goldscore has been confirmed that is the most suitable scoring function for prediction of inhibitor binding mode. Then cross docking and comparative analysis of crystal structure determined that the prediction of binding mode of inhibitors are affected by G-loop flexibility as well as the orientation of the side chains of Lys67and Glu89.
Chapter4The binding mode of lead inhibitors SMI-4a was predicted and identified. Firstly, two different binding modes of SMI-4a were obtained by molecular docking, and then the two different complex structures of SMI-4a/PIM-1kinase were calculated by molecular dynamics simulation. Subsequently, the correspondingly binding free energies were estimated with the Molecular Mechanics-Poisson Boltzmann surface area (MM-PBSA) approach. Moreover, through analyzing the computed MM/PBSA results, the preferential binding mode was determined.
Chapter5The inhibition mechanism of isoxazole quinoline-diones as PIM-1kinase inhibitors was studied, and new compounds were designed. Firstly, the binding modes of inhibitors were obtained by molecular docking, and the correlation between scoring and binding affinity was analyzed. Then molecular dynamics simulations of the inhibitors/PIM-1kinase complexes were conducted. Subsequently, the interaction energies of inhibitors and PIM-1kinase were calculated by linear interaction energy (LIE) approach. The LIE model was established, and the prediction accuracy of the binding affinity was analyzed. Finally, based on the binding mode and the inhibition activity of the inhibitors, the feasible optimization position of isoxazole quinoline-diones compounds was proposed, and three new compounds were designed to confirm the feasible optimization position.
Chapter6The feasibility and accuracy of linear response-MMPBSA (LR-MM-PBSA) approach to predict the binding affinity of benzothiophene pyrimidinones as PIM-1kinase inhibitors were analyzed. Firstly, the binding modes of the inhibitors were obtained by molecular docking, and the correlation between scoring and binding affinity was analyzed. Then the structures of the complexs were optimized, and the binding free energies were calculated by MM-PBSA. All the compounds were divided into training and test set, the LR-MM-PBSA model was established using the training set, and it was used to predict the binding affinity of the remaining compounds.
Chapter7The inhibition mechanism of triazolopyridines as PIM-1kinase inhibitors was analyzed by molecular docking and3D QSAR metheds. Firstly, the active conformations of the inhibitors were obtained by the molecular docking. Then CoMFA model and CoMSIA model were builded based on the docked conformations. Both the CoMFA model and CoMSIA model can successfully predict the compound activity. The inhibitive mechanism of triazolepyridines compounds was analyzed by the overlap of the active site and the three-dimensional equipotential surface map of CoMFA model and CoMSIA model.
本论文工作以PIM-1激酶抑制剂为研究对象,采用分子模拟(包括分子对接、分子动力学、结合自由能计算和三维定量构效关系等方法)研究其与PIM-1激酶的相互作用机理以及计算或预测其抑制活性,以期为设计新型、高效的PIM-1激酶抑制剂和先导化合物虚拟筛选提供理论基础和资料参考。全文共分七章：
1介绍本论文的研究背景、研究方法及研究内容。
2综述PIM-1激酶抑制剂的研究进展。
3研究PIM-1激酶残基柔性对抑制剂结合模式预测的影响。首先通过对15个PIM-1激酶抑制剂复合物进行复原对接,确定Goldscore是最适合于抑制剂结合模式预测的打分函数。然后通过交叉对接及晶体结构比较分析,确定PIM-1激酶G-loop的柔性以及Phe49、Lys67和Glu89的侧链取向影响抑制剂结合模式的预测。
4预测先导抑制剂SMI-4a的结合模式。首先采用分子对接预测先导抑制剂的结合模式,然后对获得的两种结合模式的抑制剂—PIM-1激酶复合物结构进行分子动力学模拟,最后采用分子力学—泊松—波尔兹曼表面积(]molecular mechanics-Poisson-Boltzmann surface area, MM-PBSA)方法计算并比较两种结合模式的结合自由能,推测了先导抑制剂SMI-4a的结合模式。
5研究异恶唑喹啉二酮类PIM-1激酶抑制剂的作用机理,并进行新化合物设计。首先采用分子对接获得抑制剂的结合模式,并分析对接打分与结合亲和力的相关性。然后对获得的抑制剂——PIM-1激酶复合物进行分子动力学模拟,采用线性相互作用能(Linear interaction energy, LIE)方法计算抑制剂与PIM-1激酶的相互作用能,建立LIE模型用于结合亲和力计算,并分析了LIE方法计算结合亲和力的准确性。最后基于先导抑制剂的结合模式及其抑制活性,提出了异恶唑喹啉二酮类化合物可能的优化位置,并设计了3个新的化合物进行验证。
6分析线性响应—分子力学—泊松—波尔兹曼表面积(linear response-MM-PBSA approach, LR-MM-PBSA)方法预测苯并噻吩嘧啶酮类PIM-1激酶抑制剂结合亲和力的可行性与准确性。首先采用分子对接预测该类抑制剂的结合模式,并分析对接打分与结合亲和力的相关性。然后优化复合物结构,并采用MM-PBSA计算相互作用能。用训练集建立3参数LR-MM-PBSA模型,并用于预测其余化合物的结合亲和力。
7分子对接结合三维定量构效关系(Three Dimensional Quantitative Structure-Activity Relationship,3D QSAR)研究三唑并毗啶类化合物对PIM-1激酶的抑制机理。采用分子对接获得该类抑制剂的活性构象,并基于对接构象建立比较分子力场分析(Comparative Molecular Field Analysis, CoMFA)和比较分子相似性指数分析(Comparative Molecular Similarity Index Analysis, CoMSIA)模型,得到的模型可以成功预测该类化合物的活性。同时将CoMFA和CoMSIA三维等势面图与活性位点叠合,分析了该类化合物的抑制机理。
Targeted inhibition of protein kinases has become an attractive therapeutic strategy in the treatment of cancer. Molecular simulation techniques have been widely applied to design and discovery of small molecule protein kinase inhibitors. Protooncogene PIM (Provirus Integration site for Moloney murine leukemia virus) kinases have been shown to have diverse biological roles in cell survival, proliferation, differentiation and apoptosis, as well as play an important role in tumor occurrence and development. Overexpression of the PIM-1kinase has been found that can promote cell cycle progression and inhibit apoptosis of cells. It has been confirmed that inhibition of cancer cells growth by inhibition of the PIM-1kinase, so the PIM-1kinase has been widely considered as attractive target for the development of anticancer drugs.
In this thesis, in order to provide theoretical foundation and reference for designing novel and potent inhibitors of the PIM-1kinase and virtual screening for lead discovery, the inhibition mechanism of some PIM-1kinase inhibitors were studied as well as inhibitor activity were calculated and predicted by molecular modeling, including molecular docking, molecular dynamics and binding free energy calculations, and three-dimensional quantitative structure-activity relationship (3D QSAR). The thesis included seven chapters and presented as follows:
Chapter1The research background, methodology and content of this thesis were introduced.
Chapter2The research progress of PIM-1kinase inhibitors in experimental and theoretical calculation was summarized.
Chapter3The effect of the residues flexibility of PIM-1kinase on the inhibitor binding mode prediction was studied. Firstly, through self-docking of15PIM-1kinase inhibitor complexs, Goldscore has been confirmed that is the most suitable scoring function for prediction of inhibitor binding mode. Then cross docking and comparative analysis of crystal structure determined that the prediction of binding mode of inhibitors are affected by G-loop flexibility as well as the orientation of the side chains of Lys67and Glu89.
Chapter4The binding mode of lead inhibitors SMI-4a was predicted and identified. Firstly, two different binding modes of SMI-4a were obtained by molecular docking, and then the two different complex structures of SMI-4a/PIM-1kinase were calculated by molecular dynamics simulation. Subsequently, the correspondingly binding free energies were estimated with the Molecular Mechanics-Poisson Boltzmann surface area (MM-PBSA) approach. Moreover, through analyzing the computed MM/PBSA results, the preferential binding mode was determined.
Chapter5The inhibition mechanism of isoxazole quinoline-diones as PIM-1kinase inhibitors was studied, and new compounds were designed. Firstly, the binding modes of inhibitors were obtained by molecular docking, and the correlation between scoring and binding affinity was analyzed. Then molecular dynamics simulations of the inhibitors/PIM-1kinase complexes were conducted. Subsequently, the interaction energies of inhibitors and PIM-1kinase were calculated by linear interaction energy (LIE) approach. The LIE model was established, and the prediction accuracy of the binding affinity was analyzed. Finally, based on the binding mode and the inhibition activity of the inhibitors, the feasible optimization position of isoxazole quinoline-diones compounds was proposed, and three new compounds were designed to confirm the feasible optimization position.
Chapter6The feasibility and accuracy of linear response-MMPBSA (LR-MM-PBSA) approach to predict the binding affinity of benzothiophene pyrimidinones as PIM-1kinase inhibitors were analyzed. Firstly, the binding modes of the inhibitors were obtained by molecular docking, and the correlation between scoring and binding affinity was analyzed. Then the structures of the complexs were optimized, and the binding free energies were calculated by MM-PBSA. All the compounds were divided into training and test set, the LR-MM-PBSA model was established using the training set, and it was used to predict the binding affinity of the remaining compounds.
Chapter7The inhibition mechanism of triazolopyridines as PIM-1kinase inhibitors was analyzed by molecular docking and3D QSAR metheds. Firstly, the active conformations of the inhibitors were obtained by the molecular docking. Then CoMFA model and CoMSIA model were builded based on the docked conformations. Both the CoMFA model and CoMSIA model can successfully predict the compound activity. The inhibitive mechanism of triazolepyridines compounds was analyzed by the overlap of the active site and the three-dimensional equipotential surface map of CoMFA model and CoMSIA model.
引文
[1]Ferlay J., Shin H. R., Bray F., et al. Estimates of Worldwide Burden of Cancer in 2008: Globocan 2008[J]. Int. J. Cancer,2010,127(12):2893-2917
[2]沈云婕,朱珺.新型分子靶向抗癌药物的研究进展[J].世界临床药物,2007,(5)：288-292
[3]Gyorgy K., Laszlo O., Daniel E., et al. Signal Transduction Therapy with Rationally Designed Kinase Inhibitors [J]. Curr. Signal Transduc. Ther.,2006,1:67-95
[4]Noble M. E. M., Endicott J. A., N Johnson L. Protein Kinase Inhibitors:Insights Into Drug Design From Structure[J]. Science,2004,303:1800-1805
[5]Cohen P. Protein Kinases-the Major Drug Targets of the Twenty-First Century? [J]. Nat. Rev. Drug Discov.,2002,1:309-315
[6]Arslan M. A., Kutuk O., Basaga H. Protein Kinases as Drug Targets in Cancer [J]. Curr. Cancer Drug Targ.,2006,6:623-634
[7]Capdeville R., Buchdunger E., Zimmermann J., et al. Glivec (STI571, Imatinib), a Rationally Developed, Targeted Anticancer Drug[J]. Nat. Rev. Drug Discov.,2002, 1(7):493-502
[8]Ranson M. Zd1839 (IressaTM):For More than Just Non-Small Cell Lung Cancer[J]. The Oncologist,2002,7(Supplement 4):16-24
[9]Smith J. Erlotinib:Small-Molecule Targeted Therapy in the Treatmentof Non-Small-Cell Lung Cancer[J]. Clin. Ther.,2005,27(10):1513-1534
[10]Demetri G. D., Van Oosterom A. T., Garrett C. R., et al. Efficacy and Safety of Sunitinib in Patients with Advanced Gastrointestinal Stromal Tumour After Failure of Imatinib:A Randomised Controlled Trial[J]. The Lancet,2006,368:1329-1338
[11]Christensen J. G., Zou H. Y., Arango M. E., et al. Cytoreductive Antitumor Activity of PF-2341066, a Novel Inhibitor of Anaplastic Lymphoma Kinase and c-MET, in Experimental Models of Anaplastic Large-Cell Lymphoma[J]. Mol. Cancer Ther.,2007, 6(12):3314-3322
[12]Stegmeier F., Warmuth M., Sellers W. R., et al. Targeted Cancer Therapies in the Twenty-First Century:Lessons From Imatinib[J]. Clin. Pharmacol. Ther.,2010,87(5): 543-552
[13]Anamika K., Gamier N., Srinivasan N. Functional Diversity of Human Protein Kinase Splice Variants Marks Significant Expansion of Human Kinome[J]. BMC Genomics. 2009,10:622
[14]杜娟.计算机辅助激酶抑制剂的分子设计和模拟[D].兰州：兰州大学,2011
[15]Theo Cuypers H., Selten G., Quint W., et al. Murine Leukemia Virus-Induced T-Cell Lymphomagenesis:Integration of Proviruses in a Distinct Chromosomal Region[J]. Cell,1984,37(1):141-150
[16]Bachmann M., Moroy T. The Serine/Threonine Kinase Pim-1[J]. Int. J. Biochem. Cell Biol.,2005,37:726-730
[17]Mikkers H., Nawijn M., Allen J., et al. Mice Deficient for All Pim Kinases Display Reduced Body Size and Impaired Responses to Hematopoietic Growth Factors[J]. Mol. Cell. Biol.,2004,24:6104-6115
[18]Nawijn M. C., Alendar A., Berns A. For Better Or for Worse:The Role of Pim Oncogenes in Tumorigenesis. [J]. Nat. Rev. Cancer,2010,11:23-34
[19]Amaravadi R., Thompson C. B. The Survival Kinases Akt and Pim as Potential Pharmacological Targets.[J]. J. Clin. Invest.,2005,115(10):2618-2624
[20]Zippo A., Robertis A. De, Serafini R., et al. Pim1-Dependent Phosphorylationof Histone H3 at Serine 10 is Required for Myc-Dependent Transcriptional Activation and Oncogenic Transformation[J]. Nat. Cell Biol.,2007,9:932-944
[21]Bachmann M., Kosan C., Xing P. X., et al. The Oncogenic Serine/Threonine Kinase Pim-1 Directly Phosphorylates and Activates the G2/M Specific Phosphatase Cdc25C[J]. Int. J. Biochem.,2006,38:430-443
[22]Zhang F., Beharry Z. M., Harris T. E., et al. Pim1 Protein Kinase Regulates Pras40 Phosphorylation and Mtor Activity in Fdcpl Cells[J]. Cancer Biol. Ther.,2009,8: 846-853
[23]Wang Z., Bhattacharya N., Weaver M., et al. Pim-1:A Serine/Threonine Kinase with a Role in Cell Survival, Proliferation, Differentiation and Tumorigenesis[J]. J. Vet. Sci, 2001,2:167-169
[24]Lilly M., Kraft A. Enforced Expression of the Mr 33,000 Pim-1 Kinase Enhances Factor-Independent Survival and Inhibits Apoptosis in Murine Myeloid Cells[J]. Cancer Res.,1997,57:5348-5355
[25]Brault L., Gasser C., Bracher F., et al. Pim Serine/Threonine Kinases in the Pathogenesis and Therapy of Hematologic Malignancies and Solid Cancers[J]. Haematologica,2010,95(6):1004-1015
[26]Cohen A. M., Grinblat B., Bessler H. Increased Expression of the Hpim-2 Gene in Human Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma[J]. Leuk Lymphoma,2004,45:951-955
[27]Claudio J. O., Masih-Kahn E., Tang H. A Molecular Compendium of Genes Expressed in Multiple Myeloma[J]. Blood,2002,100:2175-2186
[28]Popivanova B. K., Li Y. Y., Zheng H. Proto-Oncogene, Pim-3 with Serine/Threonine Kinase Activity, is Aberrantly Expressed in Human Colon Cancer Cells and Can Prevent Bad-Mediated Apoptosis[J]. Cancer Sci.,2007,98:321-328
[29]Valdman A., Fang X., Pang S. T. Pim-1 Expression in Prostatic Intraepithelial Neoplasia and Human Prostate Cancer [J]. Prostate,2004,60:367-371
[30]Li Y. Y., Popivanova B. K., Nagai Y. A Proto-Oncogene with Serine/Threonine Kinase Activity, is Aberrantly Expressed in Human Pancreatic Cancer and Phosphorylates Bad to Block Bad-Mediated Apoptosis in Human Pancreatic Cancer Cell Lines[J]. Cancer Res.,2006,66(13):6741-6747
[31]Chen J., Kobayashi M., Darmanin S., et al. Hypoxia-Mediated Up-Regulation of Pim-1 Contributes to Solid Tumor Formation[J]. Am. J. Pathol.,2009,175:400-411
[32]Wang J., Kim J., Roh M., et al. Piml Kinase Synergizes with C-Myc to Induce Advanced Prostate Carcinoma[J]. Oncogene,2010,29:2477-2487
[33]Larid P. W., Van der Lugt N. M. T., Clarke A., et al. In Vivo Analysis of Pim-1 Deficiency [J]. Nucleic Acids Res.,1993,21:4750-4755
[34]Morwick T. Pim Kinase Inhibitors:A Survey of the Patent Literature [J]. Expert Opin. Ther. Pat.,2010,20:193-212
[35]Anizon F., Shtil A. A., Danilenko V. N., et al. Fighting Tumor Cell Survival:Advances in the Design and Evaluation of Pim Inhibitors [J]. Curr. Med. Chem.,2010,17(34): 4133-4414
[36]Shah N., Pang B., Yeoh K. G., et al. Potential Roles for the Piml Kinase in Human Cancer-a Molecular and Therapeutic Appraisal[J]. Eur. J. Cancer.,2008,44:2144-2151
[37]Magnuson N. S., Wang Z., Ding G., et al. Why Target Piml for Cancer Diagnosis and Treatment?[J]. Future Oncol.,2010,6:1461-1478
[38]Batra V., Maris J. M., Kang M. H., et al. Initial Testing (Stage 1) of SGI-1776, a Piml Kinase Inhibitor, by the Pediatric Preclinical Testing Program[J]. Pediatr. Blood Cancer, 2011, Epub ahead of print
[39]秦晋.几类激酶抑制剂的分子模拟研究[D].兰州：兰州大学,2007
[40]陈敏伯.计算化学——从理论化学到分子模拟[M].北京：科学出版社,2009
[41]杨小震.分子模拟与高分子材料[M].北京：科学出版社,2002
[42]陈正隆,徐为人,汤立达.分子模拟的理论与实践[M].北京：化学工业出版社,2007
[43]胡建平.用分子模拟方法研究蛋白质受体与配体的相互作用[D].北京：北京工业大学,2008
[44]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京：化学工业出版社，2004
[45]Koga H., Itoh A., Murayama S., et al. Structure-Activity Relationships of Antibacterial 6,7-And 7,8-Disubstituted 1-Alkyl-1,4-Dibydro-4-Oxoquinoline-3-Carboxylic Acidc[J]. J. Med. Chem.,1980,23:1358-1363
[46]Kawakami Y., Moue A., Kawai T., et al. The Rationale for E2020 as a Potent Acetylcholinesterase Inhibitor[J]. Bioorg. Med. Chem.,1996,4:1429-1446
[47]von Ltzstein M., Wu W. Y., Kok G. B., et al. Rational Design of Potent Sialidase-Based Inhibitors of Influenza Virus Replication[J]. Nature,1993,363:418-423
[48]Vacca J. P., Condra J. H. Clinically Effective Hiv-1 Protease Inhibitors [J]. Drug Discov. Today,1997,2:261-272
[49]Donato N. J., Talpaz M. Clinical Use of Tyrosine Kinase Inhibitors:Therapy for Chronic Mveloeenous Leukemia and Other Cancers[J]. Clin. Cancer Res.,2000,6: 2965-2966
[50]张继龙.几类重要蛋自质的分子动力学模拟及相关抑制剂的改良[D].长春：吉林大学,2010
[51]徐筱杰,康文艺.药用天然产物[M].北京：化学工业出版社,2010
[52]康玲.药物分子对接优化模型与算法研究[D].大连：大连理工大学,2008
[53]薛颖.分子动力学模拟与自由能计算在药物分子设计中的应用[D].北京：北京工业大学,2003
[54]Kuntz I. D., Blaney J. M., Oatley S. J., et al. A Geometric Approach to Macromolecule Ligand Interactions [J]. J. Mol. Biol.,1982,161:269-288
[55]Ewing T. J. A., Makino S., Skillman A. G., et al. Dock 4.0:Search Strategies for Automated Molecular Docking of Flexible Molecule Databases[J]. J. Comput.-Aided Mol. Des.,2001,15:411-428
[56]Goodsell D. S., Morris G. M., Olson A. J. Automated Docking of Flexible Ligands: Applications of Autodock [J]. J. Mol. Recognit.,1996,9:1-5
[57]Morris G. M., Goodsell D. S., Halliday R. S., et al. Automated Docking Using a Lamarckian Genetic Algorithm and an Empirical Binding Free Energy Function[J]. J. Comput. Chem.,1998,19:1639-1662
[58]Morris G. M., Goodsell D. S., Huey R., et al. Distributed Automated Docking of Flexible Ligands to Proteins:Parallel Applications of Autodock 2.4[J]. J. Comput.-Aided Mol. Des.,1996,10:293-304
[59]Trott O., Olson A. J. Autodock Vina:Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading[J]. J. Comp. Chem.,2010,31:455-461
[60]Luty B. A., Wasserman Z. R., Stouten P. F. W., et al. A Molecular Mechanics/Grid Method for Evaluation of Ligand-Receptor Interactions [J]. J. Comp. Chem.,1995,16: 454-464
[61]Baxter C. A., Munray C. W., Clark D. E., et al. Flexible Docking Using Tabu Search and an Empirical Estimate of Binding Affinity[J]. Proteins:Struct. Funct. Genet.,1998, 33:367-382
[62]Rarey M., Kramer B., Lengauer T., et al. A Fast Flexible Docking Method Using an Incremental Construction Algorithm[J]. J. Mol. Biol.,1996,261:470-489
[63]Kramer B., Rarey M., Lengauer T. Evaluation of the Flexx Incremental Construction Algorithm for Protein-Ligand Docking[J]. Proteins:Struct. Funct. Genet.,1999,37: 228-241
[64]Jain A. N. Surflex-Dock 2.1:Robust Performance From Ligand Energetic Modeling, Ring Flexibility, and Knowledge-Based Search [J]. J. Comput.-Aided Mol. Des.,2007, 21:281-306
[65]Friesner R. A., Banks J. L., Murphy R. B., et al. Glide:A New Approach for Rapid, Accurate Docking and Scoring.1. Method and Assessment of Docking Accuracy[J]. J. Med. Chem.,2004,47:1739-1749
[66]Halgren T. A., Banks. R. B., Friesner A., et al. Glide:A New Approach for Rapid, Accurate Docking and Scoring.2. Enrichment Factors in Database Screening[J]. J. Med. Chem.,2004,47:1750-1759
[67]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[68]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:43-53
[69]Sousa S. F., Fernandes P. A., Ramos M. J. Protein-Ligand Docking:Current Status and Future Challenges[J]. Proteins:Struct. Funct. Genet.,2006,65:15-26
[70]Verdonk M. L., Cole J. C., Hartshorn M. J., et al. Improved Protein-Ligand Docking Using Gold[J]. Proteins:Struct. Funct. Bioinform.,2003,52(4):609-623
[71]Hartshorn M. J., Verdonk M. L., Chessari G., et al. Diverse, High-Quality Test Set for the Validation of Protein-Ligand Docking Performance[J]. J. Med. Chem.,2007,50: 726-741
[72]张娜.肝糖合成酶激酶3结构与功能的动力学研究及其抑制剂设计[D].杭州：浙江大学,2008
[73]傅毅.分子模拟及其在生物工程上的应用[D].无锡：江南大学,2010
[74]刘春莉.用分子模拟方法研究HIV-1整合酶与抑制剂及病毒DNA的相互作用[D].北京：北京工业大学，2005
[75]Stone M. The Clark Plot:A Semi-Historical Case Study[J]. J. Pharm. Phaamacol., 1980,32:81-86
[76]Mobley D. L., Dill K. A. Binding of Small-Molecule Ligands to Proteins:"What You See" is Not Always "What You Get"[J]. Structure,2009,17:489-498
[77]Gilson M. K., Zhou Huan-Xiang. Calculation of Protein-Ligand Binding Affinities[J]. Annu. Rev. Biophys. Biomol. Struct.,2007,36:21-42
[78]Singh N., Warshel A. Absolute Binding Free Energy Calculations:On the Accuracy of Computational Scoring of Protein-Ligand Interactions [J]. Proteins:Struct. Funct. Bioinform.,2010,78:1705-1723
[79]Ruiter A., Oostenbrink C. Free Energy Calculations of Protein-Ligand Interactions[J]. Curr. Opin. Chem. Biol.,2011,15:547-552
[80]Beveridge D. L., DiCapua F. M. Free Energy Via Molecular Simulation:Applications to Chemical and Biomolecular Systems[J]. Annu. Rev. Biophys. Biophys. Chem.,1989, 18:431-492
[81]Kollman P. Free Energy Calculations:Applications to Chemical and Biochemical Phenomena[J]. Chem. Rev.,1993,93:2395-2417
[82]Srinivasan J., Cheatham T. E., Cieplak P., et al. Continuum Solvent Studies of the Stability of Dna, Rna, and Phosphoramidate-Dna Helices[J]. J. Am. Chem. Soc.,1998, 120:9401-9409
[83]Kollman P. A., Massova I., Reyes C., et al. Calculating Structures and Free Energies of Complex Molecules:Combining Molecular Mechanics and Continuum Models[J]. Accounts Chem. Res.,2000,33:889-897
[84]Aqvist J., Medina C., Samuelsson J. E. A New Method for Predicting Binding Affinity in Computer-Aided Drug Design[J]. Protein Eng.,1994,7:385-391
[85]Hansson T., Aqvist J. Estimation of Binding Free Energies for HIV Proteinase Inhibitors by Molecular Dynamics Simulations[J]. Protein Eng.,1995,8:1137-1144
[86]Hansson T., Marelius J., Aqvist J. Ligand Binding Affinity Prediction by Linear Interaction Energy Methods[J]. J. Comput.-Aided Mol. Des.,1998,12:27-35
[87]Carlsson J., Boukharta L., Aqvist J. Combining Docking, Molecular Dynamics and the Linear Interaction Energy Method to Predict Binding Modes and Affinities for Non-Nucleoside Inhibitors to Hiv-1 Reverse Transcriptase[J]. J. Med. Chem.,2008,51: 2648-2656
[88]Bortolato A., Moro S. In Silico Binding Free Energy Predictability by Using the Linear Interaction Energy (LIE) Method:Bromobenzimidazole CK2 Inhibitors as a Case Study[J]. J. Chem. Inf. Model.,2007,47:572-582
[89]Chilin A., Battistutta R., Bortolato A., et al. Coumarin as Attractive Casein Kinase 2 (CK2) Inhibitor Scaffold:An Integrate Approach to Elucidate the Putative Binding Motif and Explain Structure-Activity Relationships[J]. J. Med. Chem.,2008,51: 752-759
[90]Kolb P., Huang D., Dey F., et al. Discovery of Kinase Inhibitors by High-Throughput Docking and Scoring Based On a Transferable Linear Interaction Energy Mode[J]. J. Med. Chem.,2008,51:1179-1188
[91]Ekonomiuk D., Su X., Ozawa K., et al. Discovery of a Non-Peptidic Inhibitor of West Nile Virus Ns3 Protease by High-Throughput Docking[J]. PLoS neglect. Trop. Dis., 2009,3:1-9
[92]Kolb P., Kipouros C. B., Huang D., et al. Structure-Based Tailoring of Compound Libraries for High-Throughput Screening:Discovery of Novel Ephb4 Kinase Inhibitors[J]. Proteins:Struct. Funct. Bioinform.,2008,73:11-18
[93]Zhou Z., Madura J. D. Relative Free Energy of Binding and Binding Mode Calculations of HIV-1 RT Inhibitors Based On Dock-MM-PB/GS[J]. Proteins:Struct. Funct. Bioinform.,2004,57:493-503
[94]Zhou Z., Bates M., Madura J. D. Structure Modeling, Ligand Binding, and Binding Affinity Calculation (LR-MM-PBSA) of Human Heparanase for Inhibition and Drug Design[J]. Proteins:Struct. Funct. Bioinform.,2006,65:580-592
[95]Zhou Z., Wang Y., Bryant S. H. Computational Analysis of the Cathepsin B Inhibitors Activities through LR-MMPBSA Binding Affinity Calculation Based On Docked Complex[J]. J. Comput. Chem.,2009,30(14):2165-2175
[96]Wichapong K., Lawson M., Pianwanit S., et al. Postprocessing of Protein-Ligand Docking Poses Using Linear Response MM-PB/SA:Application to Weel Kinase Inhibitors[J]. J. Chem. Inf. Model.,2010,50:1574-1588
[97]Cramer R. D., Patterson D. E., Bunce J. D. Comparative Molecular Field Analysis (CoMFA).1. Effect of Shape On Binding of Steroids to Carrier Proteins[J]. J. Am. Chem. Soc.,1988,110:5959-5967
[98]Cramer R. D., Bunce J. D., Patterson D. E., et al. Crossvalidation, Bootstrapping,and Partial Least Squares Compared with Multiple Regression in Conventional Qsar Studies[J]. Ouant. Struct.-Act. Relat.,1988,7:18-25
[99]Klebe G., Abraham U., Mietzner T. Molecular Similarity Indices in a Comparative Analysis (CoMSIA) of Drug Molecules to Correlate and Predict their Biological Activity[J]. J. Med. Chem,1994,37:4130-4146
[100]Muegge I., Podlogar B. L.3D-Quantitative Structure Activity Relationships of Biphenyl Carboxylic Acid Mmp-3 Inhibitors:Exploring Automated Docking as Alignment Method[J]. Ouant. Struct.-Act. Relat.,2001,20:215-222
[101]Cichero E., Cesarini S., Fossa P., et al. Thiocarbamates as Non-Nucleoside Hiv-1 Reverse Transcriptase Inhibitors:Docking-Based CoMFA and CoMSIA Analyses[J]. Eur. J. Med. Chem.,2009,44(5):2059-2070
[102]Gupta P., Roy N., Garg P. Docking-Based 3D-QSAR Study of HIV-1 Integrase Inhibitors[J]. Eur. J. Med. Chem.,2009,44(11):4276-4287
[103]Carlson H. A. Protein Flexibility is an Important Component of Structure-Based Drug Discovery[J]. Curr. Pharm. Des.,2002,8(17):1571-1578
[1]Nawijn M. C., Alendar A., Berns A. For Better Or for Worse:The Role of Pim Oncogenes in Tumorigenesis[J]. Nat. Rev. Cancer,2010,11:23-34
[2]Amaravadi R., Thompson C. B. The Survival Kinases Akt and Pim as Potential Pharmacological Targets[J]. J. Clin. Invest.,2005,115(10):2618-2624
[3]Zippo A., Robertis A. De, Serafini R., et al. Pim 1-Dependent Phosphorylationof Histone H3 at Serine 10 is Required for Myc-Dependent Transcriptional Activation and Oncogenic Transformation[J]. Nat. Cell Biol.,2007,9:932-944
[4]Bachmann M., Kosan C., Xing P. X., et al. The Oncogenic Serine/Threonine Kinase Pim-1 Directly Phosphorylates and Activates the G2/M Specific Phosphatase Cdc25C[J]. Int. J. Biochem.,2006,38:430-443
[5]Zhang F., Beharry Z. M., Harris T. E., et al. Piml Protein Kinase Regulates Pras40 Phosphorylation and Mtor Activity in Fdcpl Cells[J]. Cancer Biol. Ther.,2009,8: 846-853
[6]Wang Z., Bhattacharya N., Weaver M., et al. Pim-1:A Serine/Threonine Kinase with a Role in Cell Survival, Proliferation, Differentiation and Tumorigenesis[J]. J. Vet. Sci, 2001,2:167-169
[7]Lilly M., Kraft A. Enforced Expression of the Mr 33,000 Pim-1 Kinase Enhances Factor-Independent Survival and Inhibits Apoptosis in Murine Myeloid Cells[J]. Cancer Res.,1997,57:5348-5355
[8]Brault L., Gasser C., Bracher F., et al. Pim Serine/Threonine Kinases in the Pathogenesis and Therapy of Hematologic Malignancies and Solid Cancers[J]. Haematologica,2010, 95(6):1004-1015
[9]Cohen A. M., Grinblat B., Bessler H. Increased Expression of the Hpim-2 Gene in Human Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma[J]. Leuk. Lymphoma,2004,45:951-955
[10]Claudio J. O., Masih-Kahn E., Tang H. A Molecular Compendium of Genes Expressed in Multiple Myeloma[J]. Blood,2002,100:2175-2186
[11]Popivanova B. K., Li Y. Y., Zheng H. Proto-Oncogene, Pim-3 with Serine/Threonine Kinase Activity, is Aberrantly Expressed in Human Colon Cancer Cells and Can Prevent Bad-Mediated Apoptosis[J]. Cancer Sci.,2007,98:321-328
[12]Valdman A., Fang X., Pang S. T. Pim-1 Expression in Prostatic Intraepithelial Neoplasia and Human Prostate Cancer[J]. Prostate,2004,60:367-371
[13]Li Y. Y., Popivanova B. K., Nagai Y. A Proto-Oncogene with Serine/Threonine Kinase Activity, is Aberrantly Expressed in Human Pancreatic Cancer and Phosphorylates Bad to Block Bad-Mediated Apoptosis in Human Pancreatic Cancer Cell Lines[J]. Cancer Res.,2006,66:6741-6747
[14]Chen J., Kobayashi M., Darmanin S., et al. Hypoxia-Mediated Up-Regulation of Pim-1 Contributes to Solid Tumor Formation[J]. Am. J. Pathol.,2009,175:400-411
[15]Wang J., Kim J., Roh M., et al. Piml Kinase Synergizes with C-Myc to Induce Advanced Prostate Carcinoma[J]. Oncogene,2010,29:2477-2487
[16]Larid P. W., Van der Lugt N. M. T., Clarke A., et al. In Vivo Analysis of Pim-1 Deficiency [J]. Nucleic Acids Res.,1993,21:4750-4755
[17]Morwick T. Pim Kinase Inhibitors:A Survey of the Patent Literature [J]. Expert Opin. Ther. Pat.,2010,20:193-212
[18]Anizon F., Shtil A. A., Danilenko V. N., et al. Fighting Tumor Cell Survival:Advances in the Design and Evaluation of Pim Inhibitors [J]. Curr. Med. Chem.,2010,17(34): 4133-4414
[19]Shah N., Pang B., Yeoh K. G., et al. Potential Roles for the Piml Kinase in Human Cancer-a Molecular and Therapeutic Appraisal[J]. Eur. J. Cancer.,2008,44:2144-2151
[20]Magnuson N. S., Wang Z., Ding G., et al. Why Target Piml for Cancer Diagnosis and Treatment?[J]. Future Oncol.,2010,6:1461-1478
[21]Debreczeni J. E., Bullock A. N., Atilla G. E., et al. Ruthenium Half-Sandwich Complexes Bound to Protein Kinase Pim-1 [J]. Angew. Chem. Int. Ed. Engl.,2006,45: 1580-1585
[22]Maksimoska J., Williams D. S., Atilla-Gokcumen G. E., et al. Similar Biological Activities of Two Isostructural Ruthenium and Osmium Complexes[J]. Chem. Eur. J., 2008,14:4816-4822
[23]Feng L., Geisselbrecht Y., Blanck S., et al. Structurally Sophisticated Octahedral Metal Complexes as Highly Selective Protein Kinase Inhibitors[J]. J. Am. Chem. Soc.,2011, 133:5976-5986
[24]Jacobs M. D., Black J., Futer O., et al. Pim-1 Ligand-Bound Structures Reveal the Mechanism of Serine/Threonine Kinase Inhibition by Ly294002 [J]. J. Biol. Chem.,2005, 280:13728-13734
[25]Fabian M. A., Biggs W. H. Ⅲ, Treiber D. K., et al. A Small Molecule-Kinase Interaction Map for Clinical Kinase Inhibitors [J]. Nat. Biotechnol.,2005,23:329-336
[26]Bullock A. N., Debreczeni J. E., Fedorov O. Y., et al. Structural Basis of Inhibitor Specificity of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim-1) Kinase[J]. J. Med. Chem.,2005,280(4):7604-7614
[27]Fedorov O., Marsden B., Pogacic V., et al. A Systematic Interaction Map of Validated Kinase Inhibitors with Ser/Thr Kinases[J]. Proc. Natl Acad. Sci. USA,2007,104: 20523-20528
[28]Holder S., Zemskova M., Zhang C., et al. Characterization of a Potent and Selective Small-Molecule Inhibitor of the Piml Kinase[J]. Mol. Cancer. Ther.,2007,6:163-172
[29]Pogacic V., Bullock A. N., Fedorov O., et al. Structural Analysis Identifies Imidazo [1, 2-b] Pyridazines as Pim Kinase Inhibitors with in Vitro Antileukemic Activity[J]. Cancer Res.,2007,67:6916-6927
[30]Batra V., Maris J. M., Kang M. H., et al. Initial Testing (Stage 1) of SGI-1776, a Piml Kinase Inhibitor, by the Pediatric Preclinical Testing Program[J]. Pediatr. Blood Cancer, 2011, Epub ahead of print
[31]Mumenthaler S. M., Ng P. Y. B., Hodge A., et al. Pharmacologic Inhibition of Pim Kinases Alters Prostate Cancer Cell Growth and Resensitizes Chemoresistant Cells to Taxanes[J]. Mol. Cancer Ther.,2009,8:2882-2893
[32]Chen L. S., Redkar S., Bearss D., et al. Pim Kinase Inhibitor, SGI-1776, Induces Apoptosis in Chronic Lymphocytic Leukemia Cells[J]. Blood,2009,114(19):4150-4157
[33]Blanco-Aparicio C., Collazo A. M. G., Oyarzabal J., et al. Pim 1 Kinase Inhibitor ETP-45299 Suppresses Cellular Proliferation and Synergizes with PI3K Inhibition[J]. Cancer Lett.,2011,300:145-153
[34]Cheney I. W., Yan S., Appleby T., et al. Identification and Structure-Activity Relationships of Substituted Pyridones as Inhibitors of Pim-1 Kinase[J]. Bioorg. Med. Chem. Lett.,2007,17:1679-1683
[35]Tong Y., Stewart K. D., Thomas S., et al. Isoxazolo[3,4-b]Quinoline-3,4(1H,9H)-Diones as Unique, Potent and Selective Inhibitors for Pim-1 and Pim-2 Kinases:Chemistry, Biological Activities, and Molecular Modeling[J]. Bioorg. Med. Chem. Lett.,2008,18: 5206-5208
[36]Xia Z., Knaak C., Ma J., et al. Synthesis and Evaluation of Novel Inhibitors of Pim-1 and Pim-2 Protein Kinases[J]. J. Med. Chem.,2009,52(1):74-86
[37]Lin Y. W., Beharry Z. M., Hill E. G., et al. A Small Molecule Inhibitor of Pim Protein Kinases Blocks the Growth of Precursor T-Cell Lymphoblastic Leukemia/Lymphoma[J]. Blood,2010,115:824-833
[38]Beharry Z., Zemskova M., Mahajan S., et al. Novel Benzylidene-Thiazolidine-2,4-Diones Inhibit Pim Protein Kinase Activity and Induce Cell Cycle Arrest in Leukemia and Prostate Cancer Cells[J]. Mol. Cancer. Ther.,2009,8(6):1473-1483
[39]Tao Z. F., Hasvold L. A., Leverson J. D., et al. Discovery of 3H-Benzo[4,5]Thieno[3,2-d] Pyrimidin-4-Ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim) Kinases[J]. J. Med. Chem.,2009,52:6621-6636
[40]Grey R., Pierce A. C., Bemis G. W., et al. Structure-Based Design of 3-Aryl-6-Amino-Triazolo[4,3-b]Pyridazine Inhibitors of Pim-1 Kinase[J]. Bioorg. Med. Chem. Lett.,2009, 19:3019-3022
[41]Akue-Gedu R., Rossignol E., Azzaro S., et al. Synthesis, Kinase Inhibitory Potencies, and in Vitro Antiproliferative Evaluation of New Pim Kinase Inhibitors [J]. J. Med. Chem.,2009,52:6369-6381
[42]Haddach M., Michaux J., Schwaebe M. K., et al. Discovery of CX-6258. A Potent, Selective, and Orally Efficacious Pan-Pim Kinases Inhibitor[J]. Med. Chem. Lett.,2012, 3:135-139
[43]Nishiguchi G. A., Atallah G., Bellamacina C., et al. Discovery of Novel 3,5-Disubstituted Indole Derivatives as Potent Inhibitors of Pim-1, Pim-2, and Pim-3 Protein Kinases[J]. Bioorg. Med. Chem. Lett.,2011,21:6366-6399
[44]Xiang Y., Hirth B., Asmussen G., et al. The Discovery of Novel Benzofuran-2-Carboxylic Acids as Potent Pim-1 Inhibitors[J]. Bioorg. Med. Chem. Lett.,2011,21: 3050-3056
[45]Huber K., Brault L., Fedorov O., et al.7,8-Dichloro-l-Oxo-B-Carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes[J]. J. Med. Chem.,2012,55:403-413
[46]Pastor J., Oyarzabal J., Saluste G., et al. Hit to Lead Evaluation of 1,2,3-Triazolo[4,5-b] Pyridines as Pim Kinase Inhibitors[J]. Bioorg. Med. Chem. Lett.,2012,22:1591-1597
[47]Lopez-Ramos M., Prudent R., Moucadel V., et al. New Potent Dual Inhibitors of CK2 and Pim Kinases:Discovery and Structural Insights[J]. Faseb. J.,2010,24:3171-3185
[48]Pierre F., Stefan E., Nedellec A. S., et al.7-(4H-1,2,4-Triazol-3-yl)Benzo[c][2,6] Naphthyridines:A Novel Class of Pim Kinase Inhibitors with Potent Cell Antiproliferative Activity[J]. Bioorg. Med. Chem. Lett.,2011,21:6687-6692
[49]Schulz M. N., Fanghanel J., Schafer M., et al. A Crystallographic Fragment Screen Identifies Cinnamic Acid Derivatives as Starting Points for Potent Pim-1 Inhibitors [J]. Acta Crystallogr. D:Biol. Crystallogr.,2011,67:156-166
[50]Pierce C. A., Jacobs M., Stuver-Moody C. Docking Study Yields Four Novel Inhibitors of the Protooncogene Pim-1 Kinase[J]. J. Med. Chem.,2008,51:1972-1975
[51]Ren X., Li L., Zheng L., et al. Discovery of Novel Pim-1 Kinase Inhibitors by a Hierarchical Multistage Virtual Screening Approach Based On Svm Model, Pharmacophore, and Molecular Docking[J]. J. Chem. Inf. Model.,2011,51:1364-1375
[52]Bachmann M., Moroy T. The Serine/Threonine Kinase Pim-1 [J]. Int. J. Biochem. Cell Biol.,2005,37:726-730
[53]Qian K. C., Wang L., Hickey E. R., et al. Structural Basis of Constitutive Activity and a Unique Nucleotide Binding Mode of Human Pim-1 Kinase[J]. J. Biol. Chem.,2005,280: 6130-6137
[54]Kumar A., Mandiyan V., Suzuki Y., et al. Crystal Structures of Proto-Oncogene Kinase Pim1:A Target of Aberrant Somatic Hypermutations in Diffuse Large Cell Lymphoma [J]. J. Mol. Biol.,2005,348:183-193
[55]Merkel A. L., Meggers E., Ocker M. Piml Kinase as a Target for Cancer Therapy[J]. Expert Opin. Investig. Drugs,2012,21(04):425-436
[56]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京：化学工业出版社，2004
[57]Kubinyi H. QSAR and 3D QSAR in Drug Design Part 2:Applications and Problems[J]. Drug Discov. Today,1997,2:538-546
[58]Holder S., Lilly M., Brown M. L. Comparative Molecular Field Analysis of Flavonoid Inhibitors of the Pim-1 Kinase[J]. Bioorg. Med. Chem.,2007,15:6463-6473
[59]Wu Y., Wang F., Yu H., et al.3D-QSAR Study On the Inhibitory Activity of Flavonoids On Pim-1 Kinase[J]. Chinese J. Struct. Chem.,2010,29(8):1147-1154
[1]Arslan M. A., Kutuk O., Basaga H. Protein Kinases as Drug Targets in Cancer[J]. Curr. Cancer Drug Targ.,2006,6(7):623-634
[2]Collins I., Workman P. New Approaches to Molecular Cancer Therapeutics[J]. Nat. Chem. Biol.,2006,2:689-700
[3]Nawijn M. C., Alendar A., Berns A. For Better Or for Worse:The Role of Pim Oncogenes in Tumorigenesis[J]. Nat. Rev. Cancer,2010,11:23-34
[4]Amaravadi R., Thompson C. B. The Survival Kinases Akt and Pim as Potential Pharmacological Targets.[J]. J. Clin. Invest.,2005,115(10):2618-2624
[5]Chen J., Kobayashi M., Darmanin S., et al. Hypoxia-Mediated Up-Regulation of Pim-1 Contributes to Solid Tumor Formation[J]. Am. J. Pathol.,2009,175:400-411
[6]Larid P. W., Van der Lugt N. M. T., Clarke A., et al. In Vivo Analysis of Pim-1 Deficiency [J]. Nucleic Acids Res.,1993,21:4750-4755
[7]Morwick T. Pim Kinase Inhibitors:A Survey of the Patent Literature [J]. Expert Opin. Ther. Pat.,2010,20:193-212
[8]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京：化学工业出版社,2004.
[9]徐筱杰,康文艺.药用天然产物[M].北京：化学工业出版社,2010
[10]Lyne P. D., Lamb M. L., Saeh J. C. Accurate Prediction of the Relative Potencies of Members of a Series of Kinase Inhibitors Using Molecular Docking and MM-GBSA Scoring[J]. J. Med. Chem.,2006,49:4805-4808
[11]Perola E., Walters W. P., Charifson P. S. A Detailed Comparison of Current Docking and Scoring Methods On Systems of Pharmaceutical Relevance[J]. Proteins:Struct. Funct. Bioinform.,2004,56:235-249
[12]Bullock A. N., Debreczeni J. E., Fedorov O. Y., et al. Structural Basis of Inhibitor Specificity of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim-1) Kinase[J]. J. Med. Chem.,2005,280(4):7604-7614
[13]Tong Y., Stewart K. D., Thomas S., et al. Isoxazolo[3,4-b]Quinoline-3,4(1H,9H)-Diones as Unique, Potent and Selective Inhibitors for Pim-1 and Pim-2 Kinases:Chemistry, Biological Activities, and Molecular Modeling[J]. Bioorg. Med. Chem. Lett.,2008,18: 5206-5208
[14]Pierce C. A., Jacobs M., Stuver-Moody C. Docking Study Yields Four Novel Inhibitors of the Protooncogene Pim-1 Kinase[J]. J. Med. Chem.,2008,51:1972-1975
[15]Ren X., Li L., Zheng L., et al. Discovery of Novel Pim-1 Kinase Inhibitors by a Hierarchical Multistage Virtual Screening Approach Based On Svm Model, Pharmacophore, and Molecular Docking[J]. J. Chem. Inf. Model,2011,51:1364-1375
[16]Xia Z., Knaak C., Ma J., et al. Synthesis and Evaluation of Novel Inhibitors of Pim-1 and Pim-2 Protein Kinases[J]. J. Med. Chem.,2009,52(1):74-86
[17]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:45-53
[18]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[19]MOE V2008.10. Chemical Computing Group Inc., Montreal Canada,2008
[20]Jacobs M. D., Black J., Futer O., et al. Pim-1 Ligand-Bound Structures Reveal the Mechanism of Serine/Threonine Kinase Inhibition by Ly294002[J]. J. Biol. Chem.,2005, 280:13728-13734
[21]Pogacic V Bullock AN Fedorov O. Structural Analysis Identifies Imidazo [1,2-B] Pyridazines as Pim Kinase Inhibitors with in Vitro Antileukemic Activity [J]. Cancer Res., 2007,67:6916-6927
[22]Holder S Zemskova M. Zhang C. Characterization of a Potent and Selective Small-Molecule Inhibitor of the Piml Kinase[J]. Mol. Cancer. Ther.,2007,6:163-172
[23]Schulz M. N., Fanghanel J., Schafer M., et al. A Crystallographic Fragment Screen Identifies Cinnamic Acid Derivatives as Starting Points for Potent Pim-1 Inhibitors [J]. Acta Crystallogr. D:Biol. Crystallogr.,2011,67:156-166
[24]Tsai J., Lee J. T., Wang W., et al. Discovery of a Selective Inhibitor of Oncogenic B-Raf Kinase with Potent Antimelanoma Activity [J]. Proc. Natl. Acad. Sci. USA.,2008,105: 3041-3046
[25]Huber K., Brault L., Fedorov O. Y., et al.7,8-Dichloro-l-Oxo-β-Carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes[J]. J. Med. Chem.,2012,55:403-413
[26]Akue-Gedu R., Rossignol E., Azzaro S., et al. Synthesis, Kinase Inhibitory Potencies, and in Vitro Antiproliferative Evaluation of New Pim Kinase Inhibitors[J]. J. Med. Chem.,2009,52:6369-6381
[27]Tao Z. F., Hasvold L. A., Leverson J. D., et al. Discovery of 3H-Benzo[4,5]Thieno[3,2-d] Pyrimidin-4-Ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim) Kinases[J]. J. Med. Chem.,2009,52:6621-6636
[28]Merkel A. L., Meggers E., Ocker M. Piml Kinase as a Target for Cancer Therapy[J]. Expert Opin. Investig. Drugs,2012,21(04):425-436
[29]Verdonk M. L., Berdini V., Hartshorn M. J., et al. Virtual Screening Using Proteinligand Docking:Avoiding Artificial Enrichment [J]. J. Chem. Inf. Comput. Sci.,2004,44: 793-806
[1]Xia Z., Knaak C., Ma J., et al. Synthesis and Evaluation of Novel Inhibitors of Pim-1 and Pim-2 Protein Kinases[J]. J. Med. Chem.,2009,52(1):74-86
[2]Lin Y. W., Beharry Z. M., Hill E. G., et al. A Small Molecule Inhibitor of Pim Protein Kinases Blocks the Growth of Precursor T-Cell Lymphoblastic Leukemia/Lymphoma[J]. Blood,2010,115:824-833
[3]Beharry Z., Zemskova M., Mahajan S., et al. Novel Benzylidene-Thiazolidine-2,4-Diones Inhibit Pim Protein Kinase Activity and Induce Cell Cycle Arrest in Leukemia and Prostate Cancer Cells[J]. Mol. Cancer. Ther.,2009,8(6):1473-1483
[4]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京：化学工业出版社，2004
[5]徐筱杰,康文艺.药用天然产物[M].北京：化学工业出版社,2010
[6]Jacobs M. D., Black J., Futer O., et al. Pim-1 Ligand-Bound Structures Reveal the Mechanism of Serine/Threonine Kinase Inhibition by Ly294002[J]. J. Biol. Chem.,2005, 280:13728-13734
[7]Fabian M. A., Biggs W. H. Ⅲ., Treiber D. K., et al. A Small Molecule-Kinase Interaction Map for Clinical Kinase Inhibitors [J]. Nat. Biotechnol.,2005,23:329-336
[8]Bullock A. N., Debreczeni J. E., Fedorov O. Y., et al. Structural Basis of Inhibitor Specificity of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim-1) Kinase[J]. J. Med. Chem.,2005,280(4):7604-7614
[9]Fedorov O., Marsden B., Pogacic V., et al. A Systematic Interaction Map of Validated Kinase Inhibitors with Ser/Thr Kinases[J]. Proc. Natl Acad. Sci. USA.,2007,104: 20523-20528
[10]Knapp S., Debreczeni J., Bullock A., et al. The Human Protein Kinase Piml in Complex with its Consensus Peptide Pimtide[J]. To be Published
[11]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:45-53
[12]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[13]MOE V2008.10. Chemical Computing Group Inc., Montreal Canada,2008
[14]Case D. A., Darden T. A., Cheatham T. E., et al. Amber 11. University of California, San Francisco,2010
[15]Wang J., Wolf R. M., Case D. A., et al. Development and Testing of a General Amber Force Field[J]. J. Comput. Chem.,2004,25:1157-1174
[16]Schmidt M. W., Baldridge K. K., Boatz J. A., et al. General Atomic and Molecular Electronic Structure System[J]. J. Comput. Chem.,1993,14:1347-1363
[17]Hornak V., Abel R., Okur A., et al. Comparison of Multiple Amber Force Fields and Development of Improved Protein Backbone Parameters [J]. Protein:Struct. Funct. Bioinform.,2006,65:712-725
[18]Wang R., Cieplak J., Kollman P. How Well Does a Restrained Electrostatic Potential (RESP) Model Perform in Calculating Conformational Energies of Organic and Biological Molecules?[J]. J. Comp. Chem.,2000,21:1049-1074
[19]Jorgensen W. L., Chandrasekhar J., Madura J. D., et al. Comparison of Simple Potential Functions for Simulating Liquid Water[J]. J. Chem. Phys.,1983,79:926-935
[20]Phillips J. C., Braun R., Wang W., et al. Scalable Molecular Dynamics with Namd[J]. J. Comput. Chem.,2005,26:1781-1802
[21]Essmann U., Perera L., Berkowitz M. L., et al. A Smooth Particle Mesh Ewald Method[J]. J. Chem. Phys.,1995,103:8577-9593
[22]Ryckaert J. P., Ciccotti G., Berendsen H. J. C. Numerical Integration of the Cartesian Equations of Motion of a System with Constraints:Molecular Dynamics of N-Alkanes[J]. J. Comput. Phys.,1977,23:327-341
[23]Pastor R. W., Brooks B. R., Szabo A. An Analysis of the Accuracy of Langevin and Molecular Dynamics Algorithms[J]. Mol. Phys.,1988,65:1049-1419
[24]Berendsen H. J. C., Postma J. P. M., van Gunsteren W. F., et al. Molecular Dynamics with Coupling to an External Bath[J]. J. Chem. Phys.,1984,81:3684-3690
[25]Humphrey W., Dalke A., Schulten K. VMD:Visual Molecular Dynamics[J]. J. Mol. Graph.,1996,14:33-38
[26]Kuhn B., Kollman P. A. Binding of a Diverse Set of Ligands to Avidin and Streptavidin: An Accurate Quantitative Prediction of their Relative Affnities by a Combination of Molecular Mechanics and Continuum Solvent Models[J]. J. Med. Chem.,2000,43: 3786-3791
[27]Wang J., Hou T., Xu X. Recent Advances in Free Energy Calculations with a Combination of Molecular Mechanics and Continuum Models[J]. Curr. Comput.-Aided Drug Des.,2006,2:287-306
[1]Tong Y., Stewart K. D., Thomas S., et al. Isoxazolo[3,4-b]Quinoline-3,4(1H,9H)-Diones as Unique, Potent and Selective Inhibitors for Pim-1 and Pim-2 Kinases:Chemistry, Biological Activities, and Molecular Modeling[J]. Bioorg. Med. Chem. Lett.,2008,18: 5206-5208
[2]Aqvist J., Medina C., Samuelsson J. E. A New Method for Predicting Binding Affinity in Computer-Aided Drug Design[J]. Protein Eng.,1994,7:385-391
[3]Hansson T., Aqvist J. Estimation of Binding Free Energies for Hiv Proteinase Inhibitors by Molecular Dynamics Simulations[J]. Protein Eng.,1995,8:1137-1144
[4]Hansson T., Marelius J., Aqvist J. Ligand Binding Affinity Prediction by Linear Interaction Energy Methods[J]. J. Comput.-Aided Mol. Des.,1998,12:27-35
[5]Almlo F M., Brandsdal B. O., Aqvist J. Binding Affinity Prediction with Different Force Fields:Examination of the Linear Interaction Energy Method[J]. J. Comput. Chem.,2004, 25:1242-1254
[6]Carlsson J., Boukharta L., Aqvist J. Combining Docking, Molecular Dynamics and the Linear Interaction Energy Method to Predict Binding Modes and Affinities for Non-Nucleoside Inhibitors to Hiv-1 Reverse Transcriptase[J]. J. Med. Chem.,2008,51: 2648-2656
[7]MOE V2008.10. Chemical Computing Group Inc., Montreal Canada,2008
[8]Jacobs M. D., Black J., Futer O., et al. Pim-1 Ligand-Bound Structures Reveal the Mechanism of Serine/Threonine Kinase Inhibition by Ly294002[J]. J. Biol. Chem.,2005, 280:13728-13734
[9]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[10]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:43-53
[11]Marelius J., Kolmodin K., Feierberg I., et al. Q:A Molecular Dynamics Program for Free Energy Calculations and Empirical Valence Bond Simulations in Biomolecular Systems [J]. J. Mol. Graphics Modell,1998, (16):213-225
[12]Jorgensen W., Chandrasekhar J., Madura J., et al. Comparison of Simple Potential Functions for Simulating Liquid Water[J]. J. Chem. Phys.,1983,79:926-935
[13]Hornak V., Abel R., Okur A., et al. Comparison of Multiple Amber Force Fields and Development of Improved Protein Backbone Parameters [J]. Proteins:Struct. Funct. Bioinform.,2006,65:712-725
[14]Wang J., Wolf R. M., Caldwell J. W., et al. Development and Testing of a General Amber Force Field[J]. J. Comput. Chem.,2004,25:1157-1174
[15]Case D. A., Darden T. A., Cheatham T. E., et al. Amber 11. University of California, San Francisco,2010
[16]Ryckaert J. P., Ciccotti G., Berendsen H. J. C. Numerical Integration of the Cartesian Equations of Motion of a System with Constraints:Molecular Dynamics of N-Alkanes[J]. J. Comput. Phys.,1977,23:327-341
[17]King G., Warshel A. A Surface Constrained All-Atom Solvent Model for Effective Simulations of Polar Solutions[J]. J. Chem. Phys.,1989,91:3647-3661
[18]Lee F. S., Warshel A. A Local Reaction Field Method for Fast Evaluation of Long-Range Electrostatic Interactions in Molecular Simulations[J]. J. Chem. Phys.,1992, 97:3100-3107
[1]Pierce C. A., Jacobs M., Stuver-Moody C. Docking Study Yields Four Novel Inhibitors of the Protooncogene Pim-1 Kinase[J]. J. Med. Chem.,2008,51:1972-1975
[2]Ren X., Li L., Zheng L., et al. Discovery of Novel Pim-1 Kinase Inhibitors by a Hierarchical Multistage Virtual Screening Approach Based On SVM Model, Pharmacophore, and Molecular Docking[J]. J. Chem. Inf. Model.,2011,51:1364-1375
[3]Klebe G. Virtual Ligand Screening:Strategies, Perspectives and Limitations [J]. Drug Discov. Today,2006,11:580-594
[4]Srinivasan J., Cheatham T. E., Cieplak P., et al. Continuum Solvent Studies of the Stability of Dna, Rna, and Phosphoramidate-DNA Helices[J]. J. Am. Chem. Soc.,1998, 120:9401-9409
[5]Kollman P. A., Massova I., Reyes C., et al. Calculating Structures and Free Energies of Complex Molecules:Combining Molecular Mechanics and Continuum Models[J]. Accounts Chem. Res.,2000,33:889-897
[6]Aqvist J., Medina C., Samuelsson J. E. A New Method for Predicting Binding Affinity in Computer-Aided Drug Design[J]. Protein Eng.,1994,7:385-391
[7]Hansson T., Aqvist J. Estimation of Binding Free Energies for Hiv Proteinase Inhibitors by Molecular Dynamics Simulations[J]. Protein Eng.,1995,8:1137-1144
[8]Hansson T., Marelius J., Aqvist J. Ligand Binding Affinity Prediction by Linear Interaction Energy Methods[J]. J. Comput.-Aided Mol. Des.,1998,12:27-35
[9]Almlo F M., Brandsdal B. O., Aqvist J. Binding Affinity Prediction with Different Force Fields:Examination of the Linear Interaction Energy Method[J]. J. Comput. Chem.,2004, 25:1242-1254
[10]Carlsson J., Boukharta L., Aqvist J. Combining Docking, Molecular Dynamics and the Linear Interaction Energy Method to Predict Binding Modes and Affinities for Non-Nucleoside Inhibitors to HIV-1 Reverse Transcriptase[J]. J. Med. Chem.,2008,51: 2648-2656
[11]Bortolato A., Moro S. In Silico Binding Free Energy Predictability by Using the Linear Interaction Energy (LIE) Method:Bromobenzimidazole CK2 Inhibitors as a Case Study[J]. J. Chem. Inf. Model.,2007,47:572-582
[12]Chilin A., Battistutta R., Bortolato A., et al. Coumarin as Attractive Casein Kinase 2 (CK2) Inhibitor Scaffold:An Integrate Approach to Elucidate the Putative Binding Motif and Explain Structure-Activity Relationships[J]. J. Med. Chem.,2008,51:752-759
[13]Kolb P., Huang D., Dey F., et al. Discovery of Kinase Inhibitors by High-Throughput Docking and Scoring Based On a Transferable Linear Interaction Energy Mode[J]. J. Med. Chem.,2008,51:1179-1188
[14]Zhou Z., Madura J. D. Relative Free Energy of Binding and Binding Mode Calculations of Hiv-1 Rt Inhibitors Based On Dock-MM-PB/GS[J]. Proteins:Struct. Funct. Bioinform.,2004,57:493-503
[15]Zhou Z., Bates M., Madura J. D. Structure Modeling, Ligand Binding, and Binding Affinity Calculation (LR-MM-PBSA) of Human Heparanase for Inhibition and Drug Design[J]. Proteins:Struct. Funct. Bioinform.,2006,65:580-592
[16]Zhou Z., Wang Y., Bryant S. H. Computational Analysis of the Cathepsin B Inhibitors Activities through Lr-Mmpbsa Binding Affinity Calculation Based On Docked Complex[J]. J. Comput. Chem.,2009,30(14):2165-2175
[17]Wichapong K., Lawson M., Pianwanit S., et al. Postprocessing of Protein-Ligand Docking Poses Using Linear Response MM-PB/SA:Application to Weel Kinase Inhibitors[J]. J. Chem. Inf. Model.,2010,50:1574-1588
[18]Tao Z. F., Hasvold L. A., Leverson J. D., et al. Discovery of 3H-Benzo[4,5]Thieno[3,2-d] Pyrimidin-4-Ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim) Kinases[J]. J. Med. Chem.,2009,52:6621-6636
[19]MOE V2008.10. Chemical Computing Group Inc., Montreal Canada,2008
[20]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:45-53
[21]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[22]Jakalian A., Jack D. B., Bayly C. I. Fast, Efficient Generation of High-Quality Atomic Charges. AM1-BCC Model:Ⅱ. Parameterization and Validation[J]. J. Comput. Chem., 2002,23:1623-1641
[23]Jakalian A., Bush B. L., Jack D. B., et al. Fast, Efficient Generation of High-Quality Atomic Charges. Aml-Bcc Model:I. Method[J]. J. Comput. Chem.,2000,21:132-146
[24]Wang J. M., Cieplak P., Kollman P. A. How Well Does a Restrained Electrostatic Potential (RESP) Model Perform in Calculating Conformational Energies of Organic and Biological Molecules?[J]. J. Comput. Chem.,2000,21:1049-1074
[25]Case D. A., Darden T. A., Cheatham T. E., et al. Amber 11. University of California, San Francisco,2010
[1]杜娟.计算机辅助激酶抑制剂的分子设计和模拟[D].兰州：兰州大学,2011
[2]秦晋.几类激酶抑制剂的分子模拟研究[D].兰州：兰州大学,2007
[3]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京：化学工业出版社,2004
[4]徐筱杰,康文艺.药用天然产物[M].北京：化学工业出版社,2010
[5]Holder S., Zemskova M., Zhang C., et al. Characterization of a Potent and Selective Small-Molecule Inhibitor of the Pim1 Kinase[J]. Mol. Cancer. Ther.,2007,6:163-172
[6]Holder S., Lilly M., Brown M. L. Comparative Molecular Field Analysis of Flavonoid Inhibitors of the Pim-1 Kinase[J]. Bioorg. Med. Chem.,2007,15:6463-6473
[7]Wu Y., Wang F., Yu H., et al.3D-QSAR Study On the Inhibitory Activity of Flavonoids On Pim-1 Kinase[J]. Chinese J. Struct. Chem.,2010,29(8):1147-1154
[8]Pastor J., Oyarzabal J., Saluste G., et al. Hit to Lead Evaluation of 1,2,3-Triazolo[4,5-b] Pyridines as Pim Kinase Inhibitors [J]. Bioorg. Med. Chem. Lett.,2012,22:1591-1597
[9]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:45-53
[10]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[11]Verma J., Khedkar V. M., Coutinho E. C.3D-OSAR in Drug Design-a Review[J]. Curr. Top. Med. Chem.,2010,10:95-115
[12]Akamatsu M. Current State and Perspectives of 3D-QSAR[J]. Curr. Top. Med. Chern, 2002,2:1381-1394
[13]Cichero E., Cesarini S., Fossa P., et al. Thiocarbamates as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors:Docking-Based CoMFA and CoMSIA Analyses[J]. Eur. J. Med. Chem.,2009,44(5):2059-2070
[14]Gupta P., Roy N., Garg P. Docking-Based 3D-QSAR Study of HIV-1 Integrase Inhibitors[J]. Eur. J. Med. Chem.,2009,44(11):4276-4287
[15]Muegge I., Podlogar B. L.3D-Quantitative Structure Activity Relationships of Biphenyl Carboxylic Acid Mmp-3 Inhibitors:Exploring Automated Docking as Alignment Method[J]. Ouant. Struct.-Act. Relat.,2001,20:215-222
[16]Cramer R. D. Ⅲ, Bunce J. D., Patterson D. E. Crossvalidation, Bootstrapping, and Partial Least Squares Compared with Multiple Regression in. Conventional QSAR Studies[J]. Quant. Stuct.-Act. Relat.,1988,7:18-25
[17]Stahle L., Wold S. Multivariate Data Analysis and Experimental Design in Biomedical Research[J]. Prog. med. chem.,1988,25:292-338
[2]沈云婕,朱珺.新型分子靶向抗癌药物的研究进展[J].世界临床药物,2007,(5)：288-292
[3]Gyorgy K., Laszlo O., Daniel E., et al. Signal Transduction Therapy with Rationally Designed Kinase Inhibitors [J]. Curr. Signal Transduc. Ther.,2006,1:67-95
[4]Noble M. E. M., Endicott J. A., N Johnson L. Protein Kinase Inhibitors:Insights Into Drug Design From Structure[J]. Science,2004,303:1800-1805
[5]Cohen P. Protein Kinases-the Major Drug Targets of the Twenty-First Century? [J]. Nat. Rev. Drug Discov.,2002,1:309-315
[6]Arslan M. A., Kutuk O., Basaga H. Protein Kinases as Drug Targets in Cancer [J]. Curr. Cancer Drug Targ.,2006,6:623-634
[7]Capdeville R., Buchdunger E., Zimmermann J., et al. Glivec (STI571, Imatinib), a Rationally Developed, Targeted Anticancer Drug[J]. Nat. Rev. Drug Discov.,2002, 1(7):493-502
[8]Ranson M. Zd1839 (IressaTM):For More than Just Non-Small Cell Lung Cancer[J]. The Oncologist,2002,7(Supplement 4):16-24
[9]Smith J. Erlotinib:Small-Molecule Targeted Therapy in the Treatmentof Non-Small-Cell Lung Cancer[J]. Clin. Ther.,2005,27(10):1513-1534
[10]Demetri G. D., Van Oosterom A. T., Garrett C. R., et al. Efficacy and Safety of Sunitinib in Patients with Advanced Gastrointestinal Stromal Tumour After Failure of Imatinib:A Randomised Controlled Trial[J]. The Lancet,2006,368:1329-1338
[11]Christensen J. G., Zou H. Y., Arango M. E., et al. Cytoreductive Antitumor Activity of PF-2341066, a Novel Inhibitor of Anaplastic Lymphoma Kinase and c-MET, in Experimental Models of Anaplastic Large-Cell Lymphoma[J]. Mol. Cancer Ther.,2007, 6(12):3314-3322
[12]Stegmeier F., Warmuth M., Sellers W. R., et al. Targeted Cancer Therapies in the Twenty-First Century:Lessons From Imatinib[J]. Clin. Pharmacol. Ther.,2010,87(5): 543-552
[13]Anamika K., Gamier N., Srinivasan N. Functional Diversity of Human Protein Kinase Splice Variants Marks Significant Expansion of Human Kinome[J]. BMC Genomics. 2009,10:622
[14]杜娟.计算机辅助激酶抑制剂的分子设计和模拟[D].兰州：兰州大学,2011
[15]Theo Cuypers H., Selten G., Quint W., et al. Murine Leukemia Virus-Induced T-Cell Lymphomagenesis:Integration of Proviruses in a Distinct Chromosomal Region[J]. Cell,1984,37(1):141-150
[16]Bachmann M., Moroy T. The Serine/Threonine Kinase Pim-1[J]. Int. J. Biochem. Cell Biol.,2005,37:726-730
[17]Mikkers H., Nawijn M., Allen J., et al. Mice Deficient for All Pim Kinases Display Reduced Body Size and Impaired Responses to Hematopoietic Growth Factors[J]. Mol. Cell. Biol.,2004,24:6104-6115
[18]Nawijn M. C., Alendar A., Berns A. For Better Or for Worse:The Role of Pim Oncogenes in Tumorigenesis. [J]. Nat. Rev. Cancer,2010,11:23-34
[19]Amaravadi R., Thompson C. B. The Survival Kinases Akt and Pim as Potential Pharmacological Targets.[J]. J. Clin. Invest.,2005,115(10):2618-2624
[20]Zippo A., Robertis A. De, Serafini R., et al. Pim1-Dependent Phosphorylationof Histone H3 at Serine 10 is Required for Myc-Dependent Transcriptional Activation and Oncogenic Transformation[J]. Nat. Cell Biol.,2007,9:932-944
[21]Bachmann M., Kosan C., Xing P. X., et al. The Oncogenic Serine/Threonine Kinase Pim-1 Directly Phosphorylates and Activates the G2/M Specific Phosphatase Cdc25C[J]. Int. J. Biochem.,2006,38:430-443
[22]Zhang F., Beharry Z. M., Harris T. E., et al. Pim1 Protein Kinase Regulates Pras40 Phosphorylation and Mtor Activity in Fdcpl Cells[J]. Cancer Biol. Ther.,2009,8: 846-853
[23]Wang Z., Bhattacharya N., Weaver M., et al. Pim-1:A Serine/Threonine Kinase with a Role in Cell Survival, Proliferation, Differentiation and Tumorigenesis[J]. J. Vet. Sci, 2001,2:167-169
[24]Lilly M., Kraft A. Enforced Expression of the Mr 33,000 Pim-1 Kinase Enhances Factor-Independent Survival and Inhibits Apoptosis in Murine Myeloid Cells[J]. Cancer Res.,1997,57:5348-5355
[25]Brault L., Gasser C., Bracher F., et al. Pim Serine/Threonine Kinases in the Pathogenesis and Therapy of Hematologic Malignancies and Solid Cancers[J]. Haematologica,2010,95(6):1004-1015
[26]Cohen A. M., Grinblat B., Bessler H. Increased Expression of the Hpim-2 Gene in Human Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma[J]. Leuk Lymphoma,2004,45:951-955
[27]Claudio J. O., Masih-Kahn E., Tang H. A Molecular Compendium of Genes Expressed in Multiple Myeloma[J]. Blood,2002,100:2175-2186
[28]Popivanova B. K., Li Y. Y., Zheng H. Proto-Oncogene, Pim-3 with Serine/Threonine Kinase Activity, is Aberrantly Expressed in Human Colon Cancer Cells and Can Prevent Bad-Mediated Apoptosis[J]. Cancer Sci.,2007,98:321-328
[29]Valdman A., Fang X., Pang S. T. Pim-1 Expression in Prostatic Intraepithelial Neoplasia and Human Prostate Cancer [J]. Prostate,2004,60:367-371
[30]Li Y. Y., Popivanova B. K., Nagai Y. A Proto-Oncogene with Serine/Threonine Kinase Activity, is Aberrantly Expressed in Human Pancreatic Cancer and Phosphorylates Bad to Block Bad-Mediated Apoptosis in Human Pancreatic Cancer Cell Lines[J]. Cancer Res.,2006,66(13):6741-6747
[31]Chen J., Kobayashi M., Darmanin S., et al. Hypoxia-Mediated Up-Regulation of Pim-1 Contributes to Solid Tumor Formation[J]. Am. J. Pathol.,2009,175:400-411
[32]Wang J., Kim J., Roh M., et al. Piml Kinase Synergizes with C-Myc to Induce Advanced Prostate Carcinoma[J]. Oncogene,2010,29:2477-2487
[33]Larid P. W., Van der Lugt N. M. T., Clarke A., et al. In Vivo Analysis of Pim-1 Deficiency [J]. Nucleic Acids Res.,1993,21:4750-4755
[34]Morwick T. Pim Kinase Inhibitors:A Survey of the Patent Literature [J]. Expert Opin. Ther. Pat.,2010,20:193-212
[35]Anizon F., Shtil A. A., Danilenko V. N., et al. Fighting Tumor Cell Survival:Advances in the Design and Evaluation of Pim Inhibitors [J]. Curr. Med. Chem.,2010,17(34): 4133-4414
[36]Shah N., Pang B., Yeoh K. G., et al. Potential Roles for the Piml Kinase in Human Cancer-a Molecular and Therapeutic Appraisal[J]. Eur. J. Cancer.,2008,44:2144-2151
[37]Magnuson N. S., Wang Z., Ding G., et al. Why Target Piml for Cancer Diagnosis and Treatment?[J]. Future Oncol.,2010,6:1461-1478
[38]Batra V., Maris J. M., Kang M. H., et al. Initial Testing (Stage 1) of SGI-1776, a Piml Kinase Inhibitor, by the Pediatric Preclinical Testing Program[J]. Pediatr. Blood Cancer, 2011, Epub ahead of print
[39]秦晋.几类激酶抑制剂的分子模拟研究[D].兰州：兰州大学,2007
[40]陈敏伯.计算化学——从理论化学到分子模拟[M].北京：科学出版社,2009
[41]杨小震.分子模拟与高分子材料[M].北京：科学出版社,2002
[42]陈正隆,徐为人,汤立达.分子模拟的理论与实践[M].北京：化学工业出版社,2007
[43]胡建平.用分子模拟方法研究蛋白质受体与配体的相互作用[D].北京：北京工业大学,2008
[44]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京：化学工业出版社，2004
[45]Koga H., Itoh A., Murayama S., et al. Structure-Activity Relationships of Antibacterial 6,7-And 7,8-Disubstituted 1-Alkyl-1,4-Dibydro-4-Oxoquinoline-3-Carboxylic Acidc[J]. J. Med. Chem.,1980,23:1358-1363
[46]Kawakami Y., Moue A., Kawai T., et al. The Rationale for E2020 as a Potent Acetylcholinesterase Inhibitor[J]. Bioorg. Med. Chem.,1996,4:1429-1446
[47]von Ltzstein M., Wu W. Y., Kok G. B., et al. Rational Design of Potent Sialidase-Based Inhibitors of Influenza Virus Replication[J]. Nature,1993,363:418-423
[48]Vacca J. P., Condra J. H. Clinically Effective Hiv-1 Protease Inhibitors [J]. Drug Discov. Today,1997,2:261-272
[49]Donato N. J., Talpaz M. Clinical Use of Tyrosine Kinase Inhibitors:Therapy for Chronic Mveloeenous Leukemia and Other Cancers[J]. Clin. Cancer Res.,2000,6: 2965-2966
[50]张继龙.几类重要蛋自质的分子动力学模拟及相关抑制剂的改良[D].长春：吉林大学,2010
[51]徐筱杰,康文艺.药用天然产物[M].北京：化学工业出版社,2010
[52]康玲.药物分子对接优化模型与算法研究[D].大连：大连理工大学,2008
[53]薛颖.分子动力学模拟与自由能计算在药物分子设计中的应用[D].北京：北京工业大学,2003
[54]Kuntz I. D., Blaney J. M., Oatley S. J., et al. A Geometric Approach to Macromolecule Ligand Interactions [J]. J. Mol. Biol.,1982,161:269-288
[55]Ewing T. J. A., Makino S., Skillman A. G., et al. Dock 4.0:Search Strategies for Automated Molecular Docking of Flexible Molecule Databases[J]. J. Comput.-Aided Mol. Des.,2001,15:411-428
[56]Goodsell D. S., Morris G. M., Olson A. J. Automated Docking of Flexible Ligands: Applications of Autodock [J]. J. Mol. Recognit.,1996,9:1-5
[57]Morris G. M., Goodsell D. S., Halliday R. S., et al. Automated Docking Using a Lamarckian Genetic Algorithm and an Empirical Binding Free Energy Function[J]. J. Comput. Chem.,1998,19:1639-1662
[58]Morris G. M., Goodsell D. S., Huey R., et al. Distributed Automated Docking of Flexible Ligands to Proteins:Parallel Applications of Autodock 2.4[J]. J. Comput.-Aided Mol. Des.,1996,10:293-304
[59]Trott O., Olson A. J. Autodock Vina:Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading[J]. J. Comp. Chem.,2010,31:455-461
[60]Luty B. A., Wasserman Z. R., Stouten P. F. W., et al. A Molecular Mechanics/Grid Method for Evaluation of Ligand-Receptor Interactions [J]. J. Comp. Chem.,1995,16: 454-464
[61]Baxter C. A., Munray C. W., Clark D. E., et al. Flexible Docking Using Tabu Search and an Empirical Estimate of Binding Affinity[J]. Proteins:Struct. Funct. Genet.,1998, 33:367-382
[62]Rarey M., Kramer B., Lengauer T., et al. A Fast Flexible Docking Method Using an Incremental Construction Algorithm[J]. J. Mol. Biol.,1996,261:470-489
[63]Kramer B., Rarey M., Lengauer T. Evaluation of the Flexx Incremental Construction Algorithm for Protein-Ligand Docking[J]. Proteins:Struct. Funct. Genet.,1999,37: 228-241
[64]Jain A. N. Surflex-Dock 2.1:Robust Performance From Ligand Energetic Modeling, Ring Flexibility, and Knowledge-Based Search [J]. J. Comput.-Aided Mol. Des.,2007, 21:281-306
[65]Friesner R. A., Banks J. L., Murphy R. B., et al. Glide:A New Approach for Rapid, Accurate Docking and Scoring.1. Method and Assessment of Docking Accuracy[J]. J. Med. Chem.,2004,47:1739-1749
[66]Halgren T. A., Banks. R. B., Friesner A., et al. Glide:A New Approach for Rapid, Accurate Docking and Scoring.2. Enrichment Factors in Database Screening[J]. J. Med. Chem.,2004,47:1750-1759
[67]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[68]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:43-53
[69]Sousa S. F., Fernandes P. A., Ramos M. J. Protein-Ligand Docking:Current Status and Future Challenges[J]. Proteins:Struct. Funct. Genet.,2006,65:15-26
[70]Verdonk M. L., Cole J. C., Hartshorn M. J., et al. Improved Protein-Ligand Docking Using Gold[J]. Proteins:Struct. Funct. Bioinform.,2003,52(4):609-623
[71]Hartshorn M. J., Verdonk M. L., Chessari G., et al. Diverse, High-Quality Test Set for the Validation of Protein-Ligand Docking Performance[J]. J. Med. Chem.,2007,50: 726-741
[72]张娜.肝糖合成酶激酶3结构与功能的动力学研究及其抑制剂设计[D].杭州：浙江大学,2008
[73]傅毅.分子模拟及其在生物工程上的应用[D].无锡：江南大学,2010
[74]刘春莉.用分子模拟方法研究HIV-1整合酶与抑制剂及病毒DNA的相互作用[D].北京：北京工业大学，2005
[75]Stone M. The Clark Plot:A Semi-Historical Case Study[J]. J. Pharm. Phaamacol., 1980,32:81-86
[76]Mobley D. L., Dill K. A. Binding of Small-Molecule Ligands to Proteins:"What You See" is Not Always "What You Get"[J]. Structure,2009,17:489-498
[77]Gilson M. K., Zhou Huan-Xiang. Calculation of Protein-Ligand Binding Affinities[J]. Annu. Rev. Biophys. Biomol. Struct.,2007,36:21-42
[78]Singh N., Warshel A. Absolute Binding Free Energy Calculations:On the Accuracy of Computational Scoring of Protein-Ligand Interactions [J]. Proteins:Struct. Funct. Bioinform.,2010,78:1705-1723
[79]Ruiter A., Oostenbrink C. Free Energy Calculations of Protein-Ligand Interactions[J]. Curr. Opin. Chem. Biol.,2011,15:547-552
[80]Beveridge D. L., DiCapua F. M. Free Energy Via Molecular Simulation:Applications to Chemical and Biomolecular Systems[J]. Annu. Rev. Biophys. Biophys. Chem.,1989, 18:431-492
[81]Kollman P. Free Energy Calculations:Applications to Chemical and Biochemical Phenomena[J]. Chem. Rev.,1993,93:2395-2417
[82]Srinivasan J., Cheatham T. E., Cieplak P., et al. Continuum Solvent Studies of the Stability of Dna, Rna, and Phosphoramidate-Dna Helices[J]. J. Am. Chem. Soc.,1998, 120:9401-9409
[83]Kollman P. A., Massova I., Reyes C., et al. Calculating Structures and Free Energies of Complex Molecules:Combining Molecular Mechanics and Continuum Models[J]. Accounts Chem. Res.,2000,33:889-897
[84]Aqvist J., Medina C., Samuelsson J. E. A New Method for Predicting Binding Affinity in Computer-Aided Drug Design[J]. Protein Eng.,1994,7:385-391
[85]Hansson T., Aqvist J. Estimation of Binding Free Energies for HIV Proteinase Inhibitors by Molecular Dynamics Simulations[J]. Protein Eng.,1995,8:1137-1144
[86]Hansson T., Marelius J., Aqvist J. Ligand Binding Affinity Prediction by Linear Interaction Energy Methods[J]. J. Comput.-Aided Mol. Des.,1998,12:27-35
[87]Carlsson J., Boukharta L., Aqvist J. Combining Docking, Molecular Dynamics and the Linear Interaction Energy Method to Predict Binding Modes and Affinities for Non-Nucleoside Inhibitors to Hiv-1 Reverse Transcriptase[J]. J. Med. Chem.,2008,51: 2648-2656
[88]Bortolato A., Moro S. In Silico Binding Free Energy Predictability by Using the Linear Interaction Energy (LIE) Method:Bromobenzimidazole CK2 Inhibitors as a Case Study[J]. J. Chem. Inf. Model.,2007,47:572-582
[89]Chilin A., Battistutta R., Bortolato A., et al. Coumarin as Attractive Casein Kinase 2 (CK2) Inhibitor Scaffold:An Integrate Approach to Elucidate the Putative Binding Motif and Explain Structure-Activity Relationships[J]. J. Med. Chem.,2008,51: 752-759
[90]Kolb P., Huang D., Dey F., et al. Discovery of Kinase Inhibitors by High-Throughput Docking and Scoring Based On a Transferable Linear Interaction Energy Mode[J]. J. Med. Chem.,2008,51:1179-1188
[91]Ekonomiuk D., Su X., Ozawa K., et al. Discovery of a Non-Peptidic Inhibitor of West Nile Virus Ns3 Protease by High-Throughput Docking[J]. PLoS neglect. Trop. Dis., 2009,3:1-9
[92]Kolb P., Kipouros C. B., Huang D., et al. Structure-Based Tailoring of Compound Libraries for High-Throughput Screening:Discovery of Novel Ephb4 Kinase Inhibitors[J]. Proteins:Struct. Funct. Bioinform.,2008,73:11-18
[93]Zhou Z., Madura J. D. Relative Free Energy of Binding and Binding Mode Calculations of HIV-1 RT Inhibitors Based On Dock-MM-PB/GS[J]. Proteins:Struct. Funct. Bioinform.,2004,57:493-503
[94]Zhou Z., Bates M., Madura J. D. Structure Modeling, Ligand Binding, and Binding Affinity Calculation (LR-MM-PBSA) of Human Heparanase for Inhibition and Drug Design[J]. Proteins:Struct. Funct. Bioinform.,2006,65:580-592
[95]Zhou Z., Wang Y., Bryant S. H. Computational Analysis of the Cathepsin B Inhibitors Activities through LR-MMPBSA Binding Affinity Calculation Based On Docked Complex[J]. J. Comput. Chem.,2009,30(14):2165-2175
[96]Wichapong K., Lawson M., Pianwanit S., et al. Postprocessing of Protein-Ligand Docking Poses Using Linear Response MM-PB/SA:Application to Weel Kinase Inhibitors[J]. J. Chem. Inf. Model.,2010,50:1574-1588
[97]Cramer R. D., Patterson D. E., Bunce J. D. Comparative Molecular Field Analysis (CoMFA).1. Effect of Shape On Binding of Steroids to Carrier Proteins[J]. J. Am. Chem. Soc.,1988,110:5959-5967
[98]Cramer R. D., Bunce J. D., Patterson D. E., et al. Crossvalidation, Bootstrapping,and Partial Least Squares Compared with Multiple Regression in Conventional Qsar Studies[J]. Ouant. Struct.-Act. Relat.,1988,7:18-25
[99]Klebe G., Abraham U., Mietzner T. Molecular Similarity Indices in a Comparative Analysis (CoMSIA) of Drug Molecules to Correlate and Predict their Biological Activity[J]. J. Med. Chem,1994,37:4130-4146
[100]Muegge I., Podlogar B. L.3D-Quantitative Structure Activity Relationships of Biphenyl Carboxylic Acid Mmp-3 Inhibitors:Exploring Automated Docking as Alignment Method[J]. Ouant. Struct.-Act. Relat.,2001,20:215-222
[101]Cichero E., Cesarini S., Fossa P., et al. Thiocarbamates as Non-Nucleoside Hiv-1 Reverse Transcriptase Inhibitors:Docking-Based CoMFA and CoMSIA Analyses[J]. Eur. J. Med. Chem.,2009,44(5):2059-2070
[102]Gupta P., Roy N., Garg P. Docking-Based 3D-QSAR Study of HIV-1 Integrase Inhibitors[J]. Eur. J. Med. Chem.,2009,44(11):4276-4287
[103]Carlson H. A. Protein Flexibility is an Important Component of Structure-Based Drug Discovery[J]. Curr. Pharm. Des.,2002,8(17):1571-1578
[1]Nawijn M. C., Alendar A., Berns A. For Better Or for Worse:The Role of Pim Oncogenes in Tumorigenesis[J]. Nat. Rev. Cancer,2010,11:23-34
[2]Amaravadi R., Thompson C. B. The Survival Kinases Akt and Pim as Potential Pharmacological Targets[J]. J. Clin. Invest.,2005,115(10):2618-2624
[3]Zippo A., Robertis A. De, Serafini R., et al. Pim 1-Dependent Phosphorylationof Histone H3 at Serine 10 is Required for Myc-Dependent Transcriptional Activation and Oncogenic Transformation[J]. Nat. Cell Biol.,2007,9:932-944
[4]Bachmann M., Kosan C., Xing P. X., et al. The Oncogenic Serine/Threonine Kinase Pim-1 Directly Phosphorylates and Activates the G2/M Specific Phosphatase Cdc25C[J]. Int. J. Biochem.,2006,38:430-443
[5]Zhang F., Beharry Z. M., Harris T. E., et al. Piml Protein Kinase Regulates Pras40 Phosphorylation and Mtor Activity in Fdcpl Cells[J]. Cancer Biol. Ther.,2009,8: 846-853
[6]Wang Z., Bhattacharya N., Weaver M., et al. Pim-1:A Serine/Threonine Kinase with a Role in Cell Survival, Proliferation, Differentiation and Tumorigenesis[J]. J. Vet. Sci, 2001,2:167-169
[7]Lilly M., Kraft A. Enforced Expression of the Mr 33,000 Pim-1 Kinase Enhances Factor-Independent Survival and Inhibits Apoptosis in Murine Myeloid Cells[J]. Cancer Res.,1997,57:5348-5355
[8]Brault L., Gasser C., Bracher F., et al. Pim Serine/Threonine Kinases in the Pathogenesis and Therapy of Hematologic Malignancies and Solid Cancers[J]. Haematologica,2010, 95(6):1004-1015
[9]Cohen A. M., Grinblat B., Bessler H. Increased Expression of the Hpim-2 Gene in Human Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma[J]. Leuk. Lymphoma,2004,45:951-955
[10]Claudio J. O., Masih-Kahn E., Tang H. A Molecular Compendium of Genes Expressed in Multiple Myeloma[J]. Blood,2002,100:2175-2186
[11]Popivanova B. K., Li Y. Y., Zheng H. Proto-Oncogene, Pim-3 with Serine/Threonine Kinase Activity, is Aberrantly Expressed in Human Colon Cancer Cells and Can Prevent Bad-Mediated Apoptosis[J]. Cancer Sci.,2007,98:321-328
[12]Valdman A., Fang X., Pang S. T. Pim-1 Expression in Prostatic Intraepithelial Neoplasia and Human Prostate Cancer[J]. Prostate,2004,60:367-371
[13]Li Y. Y., Popivanova B. K., Nagai Y. A Proto-Oncogene with Serine/Threonine Kinase Activity, is Aberrantly Expressed in Human Pancreatic Cancer and Phosphorylates Bad to Block Bad-Mediated Apoptosis in Human Pancreatic Cancer Cell Lines[J]. Cancer Res.,2006,66:6741-6747
[14]Chen J., Kobayashi M., Darmanin S., et al. Hypoxia-Mediated Up-Regulation of Pim-1 Contributes to Solid Tumor Formation[J]. Am. J. Pathol.,2009,175:400-411
[15]Wang J., Kim J., Roh M., et al. Piml Kinase Synergizes with C-Myc to Induce Advanced Prostate Carcinoma[J]. Oncogene,2010,29:2477-2487
[16]Larid P. W., Van der Lugt N. M. T., Clarke A., et al. In Vivo Analysis of Pim-1 Deficiency [J]. Nucleic Acids Res.,1993,21:4750-4755
[17]Morwick T. Pim Kinase Inhibitors:A Survey of the Patent Literature [J]. Expert Opin. Ther. Pat.,2010,20:193-212
[18]Anizon F., Shtil A. A., Danilenko V. N., et al. Fighting Tumor Cell Survival:Advances in the Design and Evaluation of Pim Inhibitors [J]. Curr. Med. Chem.,2010,17(34): 4133-4414
[19]Shah N., Pang B., Yeoh K. G., et al. Potential Roles for the Piml Kinase in Human Cancer-a Molecular and Therapeutic Appraisal[J]. Eur. J. Cancer.,2008,44:2144-2151
[20]Magnuson N. S., Wang Z., Ding G., et al. Why Target Piml for Cancer Diagnosis and Treatment?[J]. Future Oncol.,2010,6:1461-1478
[21]Debreczeni J. E., Bullock A. N., Atilla G. E., et al. Ruthenium Half-Sandwich Complexes Bound to Protein Kinase Pim-1 [J]. Angew. Chem. Int. Ed. Engl.,2006,45: 1580-1585
[22]Maksimoska J., Williams D. S., Atilla-Gokcumen G. E., et al. Similar Biological Activities of Two Isostructural Ruthenium and Osmium Complexes[J]. Chem. Eur. J., 2008,14:4816-4822
[23]Feng L., Geisselbrecht Y., Blanck S., et al. Structurally Sophisticated Octahedral Metal Complexes as Highly Selective Protein Kinase Inhibitors[J]. J. Am. Chem. Soc.,2011, 133:5976-5986
[24]Jacobs M. D., Black J., Futer O., et al. Pim-1 Ligand-Bound Structures Reveal the Mechanism of Serine/Threonine Kinase Inhibition by Ly294002 [J]. J. Biol. Chem.,2005, 280:13728-13734
[25]Fabian M. A., Biggs W. H. Ⅲ, Treiber D. K., et al. A Small Molecule-Kinase Interaction Map for Clinical Kinase Inhibitors [J]. Nat. Biotechnol.,2005,23:329-336
[26]Bullock A. N., Debreczeni J. E., Fedorov O. Y., et al. Structural Basis of Inhibitor Specificity of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim-1) Kinase[J]. J. Med. Chem.,2005,280(4):7604-7614
[27]Fedorov O., Marsden B., Pogacic V., et al. A Systematic Interaction Map of Validated Kinase Inhibitors with Ser/Thr Kinases[J]. Proc. Natl Acad. Sci. USA,2007,104: 20523-20528
[28]Holder S., Zemskova M., Zhang C., et al. Characterization of a Potent and Selective Small-Molecule Inhibitor of the Piml Kinase[J]. Mol. Cancer. Ther.,2007,6:163-172
[29]Pogacic V., Bullock A. N., Fedorov O., et al. Structural Analysis Identifies Imidazo [1, 2-b] Pyridazines as Pim Kinase Inhibitors with in Vitro Antileukemic Activity[J]. Cancer Res.,2007,67:6916-6927
[30]Batra V., Maris J. M., Kang M. H., et al. Initial Testing (Stage 1) of SGI-1776, a Piml Kinase Inhibitor, by the Pediatric Preclinical Testing Program[J]. Pediatr. Blood Cancer, 2011, Epub ahead of print
[31]Mumenthaler S. M., Ng P. Y. B., Hodge A., et al. Pharmacologic Inhibition of Pim Kinases Alters Prostate Cancer Cell Growth and Resensitizes Chemoresistant Cells to Taxanes[J]. Mol. Cancer Ther.,2009,8:2882-2893
[32]Chen L. S., Redkar S., Bearss D., et al. Pim Kinase Inhibitor, SGI-1776, Induces Apoptosis in Chronic Lymphocytic Leukemia Cells[J]. Blood,2009,114(19):4150-4157
[33]Blanco-Aparicio C., Collazo A. M. G., Oyarzabal J., et al. Pim 1 Kinase Inhibitor ETP-45299 Suppresses Cellular Proliferation and Synergizes with PI3K Inhibition[J]. Cancer Lett.,2011,300:145-153
[34]Cheney I. W., Yan S., Appleby T., et al. Identification and Structure-Activity Relationships of Substituted Pyridones as Inhibitors of Pim-1 Kinase[J]. Bioorg. Med. Chem. Lett.,2007,17:1679-1683
[35]Tong Y., Stewart K. D., Thomas S., et al. Isoxazolo[3,4-b]Quinoline-3,4(1H,9H)-Diones as Unique, Potent and Selective Inhibitors for Pim-1 and Pim-2 Kinases:Chemistry, Biological Activities, and Molecular Modeling[J]. Bioorg. Med. Chem. Lett.,2008,18: 5206-5208
[36]Xia Z., Knaak C., Ma J., et al. Synthesis and Evaluation of Novel Inhibitors of Pim-1 and Pim-2 Protein Kinases[J]. J. Med. Chem.,2009,52(1):74-86
[37]Lin Y. W., Beharry Z. M., Hill E. G., et al. A Small Molecule Inhibitor of Pim Protein Kinases Blocks the Growth of Precursor T-Cell Lymphoblastic Leukemia/Lymphoma[J]. Blood,2010,115:824-833
[38]Beharry Z., Zemskova M., Mahajan S., et al. Novel Benzylidene-Thiazolidine-2,4-Diones Inhibit Pim Protein Kinase Activity and Induce Cell Cycle Arrest in Leukemia and Prostate Cancer Cells[J]. Mol. Cancer. Ther.,2009,8(6):1473-1483
[39]Tao Z. F., Hasvold L. A., Leverson J. D., et al. Discovery of 3H-Benzo[4,5]Thieno[3,2-d] Pyrimidin-4-Ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim) Kinases[J]. J. Med. Chem.,2009,52:6621-6636
[40]Grey R., Pierce A. C., Bemis G. W., et al. Structure-Based Design of 3-Aryl-6-Amino-Triazolo[4,3-b]Pyridazine Inhibitors of Pim-1 Kinase[J]. Bioorg. Med. Chem. Lett.,2009, 19:3019-3022
[41]Akue-Gedu R., Rossignol E., Azzaro S., et al. Synthesis, Kinase Inhibitory Potencies, and in Vitro Antiproliferative Evaluation of New Pim Kinase Inhibitors [J]. J. Med. Chem.,2009,52:6369-6381
[42]Haddach M., Michaux J., Schwaebe M. K., et al. Discovery of CX-6258. A Potent, Selective, and Orally Efficacious Pan-Pim Kinases Inhibitor[J]. Med. Chem. Lett.,2012, 3:135-139
[43]Nishiguchi G. A., Atallah G., Bellamacina C., et al. Discovery of Novel 3,5-Disubstituted Indole Derivatives as Potent Inhibitors of Pim-1, Pim-2, and Pim-3 Protein Kinases[J]. Bioorg. Med. Chem. Lett.,2011,21:6366-6399
[44]Xiang Y., Hirth B., Asmussen G., et al. The Discovery of Novel Benzofuran-2-Carboxylic Acids as Potent Pim-1 Inhibitors[J]. Bioorg. Med. Chem. Lett.,2011,21: 3050-3056
[45]Huber K., Brault L., Fedorov O., et al.7,8-Dichloro-l-Oxo-B-Carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes[J]. J. Med. Chem.,2012,55:403-413
[46]Pastor J., Oyarzabal J., Saluste G., et al. Hit to Lead Evaluation of 1,2,3-Triazolo[4,5-b] Pyridines as Pim Kinase Inhibitors[J]. Bioorg. Med. Chem. Lett.,2012,22:1591-1597
[47]Lopez-Ramos M., Prudent R., Moucadel V., et al. New Potent Dual Inhibitors of CK2 and Pim Kinases:Discovery and Structural Insights[J]. Faseb. J.,2010,24:3171-3185
[48]Pierre F., Stefan E., Nedellec A. S., et al.7-(4H-1,2,4-Triazol-3-yl)Benzo[c][2,6] Naphthyridines:A Novel Class of Pim Kinase Inhibitors with Potent Cell Antiproliferative Activity[J]. Bioorg. Med. Chem. Lett.,2011,21:6687-6692
[49]Schulz M. N., Fanghanel J., Schafer M., et al. A Crystallographic Fragment Screen Identifies Cinnamic Acid Derivatives as Starting Points for Potent Pim-1 Inhibitors [J]. Acta Crystallogr. D:Biol. Crystallogr.,2011,67:156-166
[50]Pierce C. A., Jacobs M., Stuver-Moody C. Docking Study Yields Four Novel Inhibitors of the Protooncogene Pim-1 Kinase[J]. J. Med. Chem.,2008,51:1972-1975
[51]Ren X., Li L., Zheng L., et al. Discovery of Novel Pim-1 Kinase Inhibitors by a Hierarchical Multistage Virtual Screening Approach Based On Svm Model, Pharmacophore, and Molecular Docking[J]. J. Chem. Inf. Model.,2011,51:1364-1375
[52]Bachmann M., Moroy T. The Serine/Threonine Kinase Pim-1 [J]. Int. J. Biochem. Cell Biol.,2005,37:726-730
[53]Qian K. C., Wang L., Hickey E. R., et al. Structural Basis of Constitutive Activity and a Unique Nucleotide Binding Mode of Human Pim-1 Kinase[J]. J. Biol. Chem.,2005,280: 6130-6137
[54]Kumar A., Mandiyan V., Suzuki Y., et al. Crystal Structures of Proto-Oncogene Kinase Pim1:A Target of Aberrant Somatic Hypermutations in Diffuse Large Cell Lymphoma [J]. J. Mol. Biol.,2005,348:183-193
[55]Merkel A. L., Meggers E., Ocker M. Piml Kinase as a Target for Cancer Therapy[J]. Expert Opin. Investig. Drugs,2012,21(04):425-436
[56]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京：化学工业出版社，2004
[57]Kubinyi H. QSAR and 3D QSAR in Drug Design Part 2:Applications and Problems[J]. Drug Discov. Today,1997,2:538-546
[58]Holder S., Lilly M., Brown M. L. Comparative Molecular Field Analysis of Flavonoid Inhibitors of the Pim-1 Kinase[J]. Bioorg. Med. Chem.,2007,15:6463-6473
[59]Wu Y., Wang F., Yu H., et al.3D-QSAR Study On the Inhibitory Activity of Flavonoids On Pim-1 Kinase[J]. Chinese J. Struct. Chem.,2010,29(8):1147-1154
[1]Arslan M. A., Kutuk O., Basaga H. Protein Kinases as Drug Targets in Cancer[J]. Curr. Cancer Drug Targ.,2006,6(7):623-634
[2]Collins I., Workman P. New Approaches to Molecular Cancer Therapeutics[J]. Nat. Chem. Biol.,2006,2:689-700
[3]Nawijn M. C., Alendar A., Berns A. For Better Or for Worse:The Role of Pim Oncogenes in Tumorigenesis[J]. Nat. Rev. Cancer,2010,11:23-34
[4]Amaravadi R., Thompson C. B. The Survival Kinases Akt and Pim as Potential Pharmacological Targets.[J]. J. Clin. Invest.,2005,115(10):2618-2624
[5]Chen J., Kobayashi M., Darmanin S., et al. Hypoxia-Mediated Up-Regulation of Pim-1 Contributes to Solid Tumor Formation[J]. Am. J. Pathol.,2009,175:400-411
[6]Larid P. W., Van der Lugt N. M. T., Clarke A., et al. In Vivo Analysis of Pim-1 Deficiency [J]. Nucleic Acids Res.,1993,21:4750-4755
[7]Morwick T. Pim Kinase Inhibitors:A Survey of the Patent Literature [J]. Expert Opin. Ther. Pat.,2010,20:193-212
[8]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京：化学工业出版社,2004.
[9]徐筱杰,康文艺.药用天然产物[M].北京：化学工业出版社,2010
[10]Lyne P. D., Lamb M. L., Saeh J. C. Accurate Prediction of the Relative Potencies of Members of a Series of Kinase Inhibitors Using Molecular Docking and MM-GBSA Scoring[J]. J. Med. Chem.,2006,49:4805-4808
[11]Perola E., Walters W. P., Charifson P. S. A Detailed Comparison of Current Docking and Scoring Methods On Systems of Pharmaceutical Relevance[J]. Proteins:Struct. Funct. Bioinform.,2004,56:235-249
[12]Bullock A. N., Debreczeni J. E., Fedorov O. Y., et al. Structural Basis of Inhibitor Specificity of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim-1) Kinase[J]. J. Med. Chem.,2005,280(4):7604-7614
[13]Tong Y., Stewart K. D., Thomas S., et al. Isoxazolo[3,4-b]Quinoline-3,4(1H,9H)-Diones as Unique, Potent and Selective Inhibitors for Pim-1 and Pim-2 Kinases:Chemistry, Biological Activities, and Molecular Modeling[J]. Bioorg. Med. Chem. Lett.,2008,18: 5206-5208
[14]Pierce C. A., Jacobs M., Stuver-Moody C. Docking Study Yields Four Novel Inhibitors of the Protooncogene Pim-1 Kinase[J]. J. Med. Chem.,2008,51:1972-1975
[15]Ren X., Li L., Zheng L., et al. Discovery of Novel Pim-1 Kinase Inhibitors by a Hierarchical Multistage Virtual Screening Approach Based On Svm Model, Pharmacophore, and Molecular Docking[J]. J. Chem. Inf. Model,2011,51:1364-1375
[16]Xia Z., Knaak C., Ma J., et al. Synthesis and Evaluation of Novel Inhibitors of Pim-1 and Pim-2 Protein Kinases[J]. J. Med. Chem.,2009,52(1):74-86
[17]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:45-53
[18]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[19]MOE V2008.10. Chemical Computing Group Inc., Montreal Canada,2008
[20]Jacobs M. D., Black J., Futer O., et al. Pim-1 Ligand-Bound Structures Reveal the Mechanism of Serine/Threonine Kinase Inhibition by Ly294002[J]. J. Biol. Chem.,2005, 280:13728-13734
[21]Pogacic V Bullock AN Fedorov O. Structural Analysis Identifies Imidazo [1,2-B] Pyridazines as Pim Kinase Inhibitors with in Vitro Antileukemic Activity [J]. Cancer Res., 2007,67:6916-6927
[22]Holder S Zemskova M. Zhang C. Characterization of a Potent and Selective Small-Molecule Inhibitor of the Piml Kinase[J]. Mol. Cancer. Ther.,2007,6:163-172
[23]Schulz M. N., Fanghanel J., Schafer M., et al. A Crystallographic Fragment Screen Identifies Cinnamic Acid Derivatives as Starting Points for Potent Pim-1 Inhibitors [J]. Acta Crystallogr. D:Biol. Crystallogr.,2011,67:156-166
[24]Tsai J., Lee J. T., Wang W., et al. Discovery of a Selective Inhibitor of Oncogenic B-Raf Kinase with Potent Antimelanoma Activity [J]. Proc. Natl. Acad. Sci. USA.,2008,105: 3041-3046
[25]Huber K., Brault L., Fedorov O. Y., et al.7,8-Dichloro-l-Oxo-β-Carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes[J]. J. Med. Chem.,2012,55:403-413
[26]Akue-Gedu R., Rossignol E., Azzaro S., et al. Synthesis, Kinase Inhibitory Potencies, and in Vitro Antiproliferative Evaluation of New Pim Kinase Inhibitors[J]. J. Med. Chem.,2009,52:6369-6381
[27]Tao Z. F., Hasvold L. A., Leverson J. D., et al. Discovery of 3H-Benzo[4,5]Thieno[3,2-d] Pyrimidin-4-Ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim) Kinases[J]. J. Med. Chem.,2009,52:6621-6636
[28]Merkel A. L., Meggers E., Ocker M. Piml Kinase as a Target for Cancer Therapy[J]. Expert Opin. Investig. Drugs,2012,21(04):425-436
[29]Verdonk M. L., Berdini V., Hartshorn M. J., et al. Virtual Screening Using Proteinligand Docking:Avoiding Artificial Enrichment [J]. J. Chem. Inf. Comput. Sci.,2004,44: 793-806
[1]Xia Z., Knaak C., Ma J., et al. Synthesis and Evaluation of Novel Inhibitors of Pim-1 and Pim-2 Protein Kinases[J]. J. Med. Chem.,2009,52(1):74-86
[2]Lin Y. W., Beharry Z. M., Hill E. G., et al. A Small Molecule Inhibitor of Pim Protein Kinases Blocks the Growth of Precursor T-Cell Lymphoblastic Leukemia/Lymphoma[J]. Blood,2010,115:824-833
[3]Beharry Z., Zemskova M., Mahajan S., et al. Novel Benzylidene-Thiazolidine-2,4-Diones Inhibit Pim Protein Kinase Activity and Induce Cell Cycle Arrest in Leukemia and Prostate Cancer Cells[J]. Mol. Cancer. Ther.,2009,8(6):1473-1483
[4]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京：化学工业出版社，2004
[5]徐筱杰,康文艺.药用天然产物[M].北京：化学工业出版社,2010
[6]Jacobs M. D., Black J., Futer O., et al. Pim-1 Ligand-Bound Structures Reveal the Mechanism of Serine/Threonine Kinase Inhibition by Ly294002[J]. J. Biol. Chem.,2005, 280:13728-13734
[7]Fabian M. A., Biggs W. H. Ⅲ., Treiber D. K., et al. A Small Molecule-Kinase Interaction Map for Clinical Kinase Inhibitors [J]. Nat. Biotechnol.,2005,23:329-336
[8]Bullock A. N., Debreczeni J. E., Fedorov O. Y., et al. Structural Basis of Inhibitor Specificity of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim-1) Kinase[J]. J. Med. Chem.,2005,280(4):7604-7614
[9]Fedorov O., Marsden B., Pogacic V., et al. A Systematic Interaction Map of Validated Kinase Inhibitors with Ser/Thr Kinases[J]. Proc. Natl Acad. Sci. USA.,2007,104: 20523-20528
[10]Knapp S., Debreczeni J., Bullock A., et al. The Human Protein Kinase Piml in Complex with its Consensus Peptide Pimtide[J]. To be Published
[11]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:45-53
[12]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[13]MOE V2008.10. Chemical Computing Group Inc., Montreal Canada,2008
[14]Case D. A., Darden T. A., Cheatham T. E., et al. Amber 11. University of California, San Francisco,2010
[15]Wang J., Wolf R. M., Case D. A., et al. Development and Testing of a General Amber Force Field[J]. J. Comput. Chem.,2004,25:1157-1174
[16]Schmidt M. W., Baldridge K. K., Boatz J. A., et al. General Atomic and Molecular Electronic Structure System[J]. J. Comput. Chem.,1993,14:1347-1363
[17]Hornak V., Abel R., Okur A., et al. Comparison of Multiple Amber Force Fields and Development of Improved Protein Backbone Parameters [J]. Protein:Struct. Funct. Bioinform.,2006,65:712-725
[18]Wang R., Cieplak J., Kollman P. How Well Does a Restrained Electrostatic Potential (RESP) Model Perform in Calculating Conformational Energies of Organic and Biological Molecules?[J]. J. Comp. Chem.,2000,21:1049-1074
[19]Jorgensen W. L., Chandrasekhar J., Madura J. D., et al. Comparison of Simple Potential Functions for Simulating Liquid Water[J]. J. Chem. Phys.,1983,79:926-935
[20]Phillips J. C., Braun R., Wang W., et al. Scalable Molecular Dynamics with Namd[J]. J. Comput. Chem.,2005,26:1781-1802
[21]Essmann U., Perera L., Berkowitz M. L., et al. A Smooth Particle Mesh Ewald Method[J]. J. Chem. Phys.,1995,103:8577-9593
[22]Ryckaert J. P., Ciccotti G., Berendsen H. J. C. Numerical Integration of the Cartesian Equations of Motion of a System with Constraints:Molecular Dynamics of N-Alkanes[J]. J. Comput. Phys.,1977,23:327-341
[23]Pastor R. W., Brooks B. R., Szabo A. An Analysis of the Accuracy of Langevin and Molecular Dynamics Algorithms[J]. Mol. Phys.,1988,65:1049-1419
[24]Berendsen H. J. C., Postma J. P. M., van Gunsteren W. F., et al. Molecular Dynamics with Coupling to an External Bath[J]. J. Chem. Phys.,1984,81:3684-3690
[25]Humphrey W., Dalke A., Schulten K. VMD:Visual Molecular Dynamics[J]. J. Mol. Graph.,1996,14:33-38
[26]Kuhn B., Kollman P. A. Binding of a Diverse Set of Ligands to Avidin and Streptavidin: An Accurate Quantitative Prediction of their Relative Affnities by a Combination of Molecular Mechanics and Continuum Solvent Models[J]. J. Med. Chem.,2000,43: 3786-3791
[27]Wang J., Hou T., Xu X. Recent Advances in Free Energy Calculations with a Combination of Molecular Mechanics and Continuum Models[J]. Curr. Comput.-Aided Drug Des.,2006,2:287-306
[1]Tong Y., Stewart K. D., Thomas S., et al. Isoxazolo[3,4-b]Quinoline-3,4(1H,9H)-Diones as Unique, Potent and Selective Inhibitors for Pim-1 and Pim-2 Kinases:Chemistry, Biological Activities, and Molecular Modeling[J]. Bioorg. Med. Chem. Lett.,2008,18: 5206-5208
[2]Aqvist J., Medina C., Samuelsson J. E. A New Method for Predicting Binding Affinity in Computer-Aided Drug Design[J]. Protein Eng.,1994,7:385-391
[3]Hansson T., Aqvist J. Estimation of Binding Free Energies for Hiv Proteinase Inhibitors by Molecular Dynamics Simulations[J]. Protein Eng.,1995,8:1137-1144
[4]Hansson T., Marelius J., Aqvist J. Ligand Binding Affinity Prediction by Linear Interaction Energy Methods[J]. J. Comput.-Aided Mol. Des.,1998,12:27-35
[5]Almlo F M., Brandsdal B. O., Aqvist J. Binding Affinity Prediction with Different Force Fields:Examination of the Linear Interaction Energy Method[J]. J. Comput. Chem.,2004, 25:1242-1254
[6]Carlsson J., Boukharta L., Aqvist J. Combining Docking, Molecular Dynamics and the Linear Interaction Energy Method to Predict Binding Modes and Affinities for Non-Nucleoside Inhibitors to Hiv-1 Reverse Transcriptase[J]. J. Med. Chem.,2008,51: 2648-2656
[7]MOE V2008.10. Chemical Computing Group Inc., Montreal Canada,2008
[8]Jacobs M. D., Black J., Futer O., et al. Pim-1 Ligand-Bound Structures Reveal the Mechanism of Serine/Threonine Kinase Inhibition by Ly294002[J]. J. Biol. Chem.,2005, 280:13728-13734
[9]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[10]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:43-53
[11]Marelius J., Kolmodin K., Feierberg I., et al. Q:A Molecular Dynamics Program for Free Energy Calculations and Empirical Valence Bond Simulations in Biomolecular Systems [J]. J. Mol. Graphics Modell,1998, (16):213-225
[12]Jorgensen W., Chandrasekhar J., Madura J., et al. Comparison of Simple Potential Functions for Simulating Liquid Water[J]. J. Chem. Phys.,1983,79:926-935
[13]Hornak V., Abel R., Okur A., et al. Comparison of Multiple Amber Force Fields and Development of Improved Protein Backbone Parameters [J]. Proteins:Struct. Funct. Bioinform.,2006,65:712-725
[14]Wang J., Wolf R. M., Caldwell J. W., et al. Development and Testing of a General Amber Force Field[J]. J. Comput. Chem.,2004,25:1157-1174
[15]Case D. A., Darden T. A., Cheatham T. E., et al. Amber 11. University of California, San Francisco,2010
[16]Ryckaert J. P., Ciccotti G., Berendsen H. J. C. Numerical Integration of the Cartesian Equations of Motion of a System with Constraints:Molecular Dynamics of N-Alkanes[J]. J. Comput. Phys.,1977,23:327-341
[17]King G., Warshel A. A Surface Constrained All-Atom Solvent Model for Effective Simulations of Polar Solutions[J]. J. Chem. Phys.,1989,91:3647-3661
[18]Lee F. S., Warshel A. A Local Reaction Field Method for Fast Evaluation of Long-Range Electrostatic Interactions in Molecular Simulations[J]. J. Chem. Phys.,1992, 97:3100-3107
[1]Pierce C. A., Jacobs M., Stuver-Moody C. Docking Study Yields Four Novel Inhibitors of the Protooncogene Pim-1 Kinase[J]. J. Med. Chem.,2008,51:1972-1975
[2]Ren X., Li L., Zheng L., et al. Discovery of Novel Pim-1 Kinase Inhibitors by a Hierarchical Multistage Virtual Screening Approach Based On SVM Model, Pharmacophore, and Molecular Docking[J]. J. Chem. Inf. Model.,2011,51:1364-1375
[3]Klebe G. Virtual Ligand Screening:Strategies, Perspectives and Limitations [J]. Drug Discov. Today,2006,11:580-594
[4]Srinivasan J., Cheatham T. E., Cieplak P., et al. Continuum Solvent Studies of the Stability of Dna, Rna, and Phosphoramidate-DNA Helices[J]. J. Am. Chem. Soc.,1998, 120:9401-9409
[5]Kollman P. A., Massova I., Reyes C., et al. Calculating Structures and Free Energies of Complex Molecules:Combining Molecular Mechanics and Continuum Models[J]. Accounts Chem. Res.,2000,33:889-897
[6]Aqvist J., Medina C., Samuelsson J. E. A New Method for Predicting Binding Affinity in Computer-Aided Drug Design[J]. Protein Eng.,1994,7:385-391
[7]Hansson T., Aqvist J. Estimation of Binding Free Energies for Hiv Proteinase Inhibitors by Molecular Dynamics Simulations[J]. Protein Eng.,1995,8:1137-1144
[8]Hansson T., Marelius J., Aqvist J. Ligand Binding Affinity Prediction by Linear Interaction Energy Methods[J]. J. Comput.-Aided Mol. Des.,1998,12:27-35
[9]Almlo F M., Brandsdal B. O., Aqvist J. Binding Affinity Prediction with Different Force Fields:Examination of the Linear Interaction Energy Method[J]. J. Comput. Chem.,2004, 25:1242-1254
[10]Carlsson J., Boukharta L., Aqvist J. Combining Docking, Molecular Dynamics and the Linear Interaction Energy Method to Predict Binding Modes and Affinities for Non-Nucleoside Inhibitors to HIV-1 Reverse Transcriptase[J]. J. Med. Chem.,2008,51: 2648-2656
[11]Bortolato A., Moro S. In Silico Binding Free Energy Predictability by Using the Linear Interaction Energy (LIE) Method:Bromobenzimidazole CK2 Inhibitors as a Case Study[J]. J. Chem. Inf. Model.,2007,47:572-582
[12]Chilin A., Battistutta R., Bortolato A., et al. Coumarin as Attractive Casein Kinase 2 (CK2) Inhibitor Scaffold:An Integrate Approach to Elucidate the Putative Binding Motif and Explain Structure-Activity Relationships[J]. J. Med. Chem.,2008,51:752-759
[13]Kolb P., Huang D., Dey F., et al. Discovery of Kinase Inhibitors by High-Throughput Docking and Scoring Based On a Transferable Linear Interaction Energy Mode[J]. J. Med. Chem.,2008,51:1179-1188
[14]Zhou Z., Madura J. D. Relative Free Energy of Binding and Binding Mode Calculations of Hiv-1 Rt Inhibitors Based On Dock-MM-PB/GS[J]. Proteins:Struct. Funct. Bioinform.,2004,57:493-503
[15]Zhou Z., Bates M., Madura J. D. Structure Modeling, Ligand Binding, and Binding Affinity Calculation (LR-MM-PBSA) of Human Heparanase for Inhibition and Drug Design[J]. Proteins:Struct. Funct. Bioinform.,2006,65:580-592
[16]Zhou Z., Wang Y., Bryant S. H. Computational Analysis of the Cathepsin B Inhibitors Activities through Lr-Mmpbsa Binding Affinity Calculation Based On Docked Complex[J]. J. Comput. Chem.,2009,30(14):2165-2175
[17]Wichapong K., Lawson M., Pianwanit S., et al. Postprocessing of Protein-Ligand Docking Poses Using Linear Response MM-PB/SA:Application to Weel Kinase Inhibitors[J]. J. Chem. Inf. Model.,2010,50:1574-1588
[18]Tao Z. F., Hasvold L. A., Leverson J. D., et al. Discovery of 3H-Benzo[4,5]Thieno[3,2-d] Pyrimidin-4-Ones as Potent, Highly Selective, and Orally Bioavailable Inhibitors of the Human Protooncogene Proviral Insertion Site in Moloney Murine Leukemia Virus (Pim) Kinases[J]. J. Med. Chem.,2009,52:6621-6636
[19]MOE V2008.10. Chemical Computing Group Inc., Montreal Canada,2008
[20]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:45-53
[21]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[22]Jakalian A., Jack D. B., Bayly C. I. Fast, Efficient Generation of High-Quality Atomic Charges. AM1-BCC Model:Ⅱ. Parameterization and Validation[J]. J. Comput. Chem., 2002,23:1623-1641
[23]Jakalian A., Bush B. L., Jack D. B., et al. Fast, Efficient Generation of High-Quality Atomic Charges. Aml-Bcc Model:I. Method[J]. J. Comput. Chem.,2000,21:132-146
[24]Wang J. M., Cieplak P., Kollman P. A. How Well Does a Restrained Electrostatic Potential (RESP) Model Perform in Calculating Conformational Energies of Organic and Biological Molecules?[J]. J. Comput. Chem.,2000,21:1049-1074
[25]Case D. A., Darden T. A., Cheatham T. E., et al. Amber 11. University of California, San Francisco,2010
[1]杜娟.计算机辅助激酶抑制剂的分子设计和模拟[D].兰州：兰州大学,2011
[2]秦晋.几类激酶抑制剂的分子模拟研究[D].兰州：兰州大学,2007
[3]徐筱杰,侯廷军,乔学斌等.计算机辅助药物分子设计[M].北京：化学工业出版社,2004
[4]徐筱杰,康文艺.药用天然产物[M].北京：化学工业出版社,2010
[5]Holder S., Zemskova M., Zhang C., et al. Characterization of a Potent and Selective Small-Molecule Inhibitor of the Pim1 Kinase[J]. Mol. Cancer. Ther.,2007,6:163-172
[6]Holder S., Lilly M., Brown M. L. Comparative Molecular Field Analysis of Flavonoid Inhibitors of the Pim-1 Kinase[J]. Bioorg. Med. Chem.,2007,15:6463-6473
[7]Wu Y., Wang F., Yu H., et al.3D-QSAR Study On the Inhibitory Activity of Flavonoids On Pim-1 Kinase[J]. Chinese J. Struct. Chem.,2010,29(8):1147-1154
[8]Pastor J., Oyarzabal J., Saluste G., et al. Hit to Lead Evaluation of 1,2,3-Triazolo[4,5-b] Pyridines as Pim Kinase Inhibitors [J]. Bioorg. Med. Chem. Lett.,2012,22:1591-1597
[9]Jones G., Willett P., Glen R. C. Molecular Recognition of Receptor Sites Using a Genetic Algorithm with a Description of Desolvation[J]. J. Mol. Biol.,1995,245:45-53
[10]Jones G., Willett P., Glen R. C., et al. Development and Validation of a Genetic Algorithm for Flexible Docking[J]. J. Mol. Biol.,1997,267:727-748
[11]Verma J., Khedkar V. M., Coutinho E. C.3D-OSAR in Drug Design-a Review[J]. Curr. Top. Med. Chem.,2010,10:95-115
[12]Akamatsu M. Current State and Perspectives of 3D-QSAR[J]. Curr. Top. Med. Chern, 2002,2:1381-1394
[13]Cichero E., Cesarini S., Fossa P., et al. Thiocarbamates as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors:Docking-Based CoMFA and CoMSIA Analyses[J]. Eur. J. Med. Chem.,2009,44(5):2059-2070
[14]Gupta P., Roy N., Garg P. Docking-Based 3D-QSAR Study of HIV-1 Integrase Inhibitors[J]. Eur. J. Med. Chem.,2009,44(11):4276-4287
[15]Muegge I., Podlogar B. L.3D-Quantitative Structure Activity Relationships of Biphenyl Carboxylic Acid Mmp-3 Inhibitors:Exploring Automated Docking as Alignment Method[J]. Ouant. Struct.-Act. Relat.,2001,20:215-222
[16]Cramer R. D. Ⅲ, Bunce J. D., Patterson D. E. Crossvalidation, Bootstrapping, and Partial Least Squares Compared with Multiple Regression in. Conventional QSAR Studies[J]. Quant. Stuct.-Act. Relat.,1988,7:18-25
[17]Stahle L., Wold S. Multivariate Data Analysis and Experimental Design in Biomedical Research[J]. Prog. med. chem.,1988,25:292-338
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |