支持向量机在药物代谢和药物的QSAR模型中的应用
摘要
作为一种数据挖掘的新方法,支持向量机已被应用于许多不同领域。我们采用SVM方法,筛选适当的分子描述符,选择并优化SVM参数,进行了CVP3A4抑制剂生物活性等数据的QSAR建模。模型经交叉验证和预测集法验证,同时偏最小二乘法和人工神经网络方法也进行建模作为比照。最终SVM方法的交叉验证相关性系数达到0.92而预测集的相关性系数为0.73.各项统计标准均优于其它回归方法所得的模型,证明SVM方法是一种较为可靠的QSAR/QSPR回归工具。同时,本文还讨论了各种回归方法对P450的Km值的预测以及嘧啶类抗疟疾药物的3D-QSAR。从各类文献中收集到不同P450酶的数百个底物的Km值数据,采用不同的回归方法分别建立了QSAR模型,并对不同的回归方法进行了比较。疟疾每年造成的死亡超过百万,据报道恶性虐原虫(Plasmodium falciparum)的甲硫氨酸氨基肽酶可能是一个潜在的抗疟药物靶点,因此我们对一系列嘧啶类衍生物进行了3D定量构效关系研究,CoMFA方法取得了不错的结果,而CoMSIA的模型则不够理想。CoMFA模型的训练集交叉验证系数q2=0.617,预测集相关性系数为0.631,说明模型的预测能力较好,对于新的抗疟药的设计可能会有所帮助。
The support vector machine (SVM) is a new method of data mining, which has been widely applied in many fields. Using this method we constructed several computational model of CYP3A4 inhibition based on the experimental IC50 values of 42 inhibitors and few molecular descriptors represented the physiochemical and structural property of compound. These models were further evaluated by the cross validation and the independent test set. The model with the highest predictive ability reached the cross validated correlation coefficient r2 of 0.92 and the predictive coefficient r2 of test set of 0.73. The predictive ability of model obtained using SVM is better compared with the models derived from the ANN and PLS methods. The results indicate that SVM can also be severed as a promising statistic tool for quantitative structure- property/ activity relationship (QSPR/QSAR) studies. We also built some model to predict the Km values of P450 substrates and a 3D-QSAR model for a series of pyrimidine derivatives. We selected hundreds of Km values of different P450 enzyme substrates from many references. We used different regression methods to build QSAR models and compare SVM models with the others. Malaria kills over 1 million people annually. It was reported that the Plasmodium falciparum methionine aminopeptidase 1b inhibitors could be potential antimalaria agents. This three dimensional quantitative structure activity relationship(3D-QSAR) model for a series of pyrimidine derivatives was developed to gain insights into design for potential new antimalaria agents. It is found the Comparative Molecular Field Analysis (CoMFA) method gives good results while the Comparative Molecular Similarity Indices Analysis(CoMSIA) is less satisfactory. The CoMFA method yields a cross–validated correlation coefficient q2 =0.617, non-cross-validated R2=0.975, SE(Standard error)=0.086 and the F ratio=94.518. It indicates that the model possesses a high predictability. The model we build may be of value in facilitating design of new potent antimalaria agents.
The support vector machine (SVM) is a new method of data mining, which has been widely applied in many fields. Using this method we constructed several computational model of CYP3A4 inhibition based on the experimental IC50 values of 42 inhibitors and few molecular descriptors represented the physiochemical and structural property of compound. These models were further evaluated by the cross validation and the independent test set. The model with the highest predictive ability reached the cross validated correlation coefficient r2 of 0.92 and the predictive coefficient r2 of test set of 0.73. The predictive ability of model obtained using SVM is better compared with the models derived from the ANN and PLS methods. The results indicate that SVM can also be severed as a promising statistic tool for quantitative structure- property/ activity relationship (QSPR/QSAR) studies. We also built some model to predict the Km values of P450 substrates and a 3D-QSAR model for a series of pyrimidine derivatives. We selected hundreds of Km values of different P450 enzyme substrates from many references. We used different regression methods to build QSAR models and compare SVM models with the others. Malaria kills over 1 million people annually. It was reported that the Plasmodium falciparum methionine aminopeptidase 1b inhibitors could be potential antimalaria agents. This three dimensional quantitative structure activity relationship(3D-QSAR) model for a series of pyrimidine derivatives was developed to gain insights into design for potential new antimalaria agents. It is found the Comparative Molecular Field Analysis (CoMFA) method gives good results while the Comparative Molecular Similarity Indices Analysis(CoMSIA) is less satisfactory. The CoMFA method yields a cross–validated correlation coefficient q2 =0.617, non-cross-validated R2=0.975, SE(Standard error)=0.086 and the F ratio=94.518. It indicates that the model possesses a high predictability. The model we build may be of value in facilitating design of new potent antimalaria agents.
引文
1.徐筱杰,侯廷军,乔学斌,章威.计算机辅助药物分子设计.化学工业出版社,北京:2004.
2. Hansch C, Muir R.C, Fujita T, Maloney P, Geiger F, Streich M (1963) The correlation of Biological Activity of Plant Growth Regulators and Chlormycetin Derivatives with Hammett Constants and Partition Coefficients. J Am Chem Soc 85:2817-2824.
3. Hansch C, Fujita T (1963)ρ-σ-πAnalysisA Method for the Correlation of Biological Activity and Chemical Structure. J Am Chem Soc 86:1616-1626.
4. Muir R, Fujita T, Hansch C (1967) Structure-Activity Relationship in the Auxin Activity of Mono-Substituted Phenylacetic Acids. Plant Physiol. 42:1519-1526.
5. Kubinyi H (1976) Quantitative Structure-Activity Relationships. 7. The Bilinear Model, a New Model for Nonlinear Dependence of Biological Activity on Hydrophobic Character. JMed Chem 20:625-629.
6. Free S H, Wilson J W (1964) A Mathematical Contribution to Structure-Activity Studies. J Med Chem 7:395-399.
7. Kubinyi H, Kehrhahn O H (1976) Quantitative Structure-Activity Relationships. 2. A Mixed Approach, Based on Hansch and Free-Wilson Analysis. J Med Chem 19:587-600.
8. Crippen G M (1979) Distance geometry approach to rationalizing binding data. J Med Chem 22:988-997.
9. Crippen G M (1980) Quantitative structure-activity relationships by distance geometry: systematic analysis of dihydrofolate reductase inhibitors. J Med Chem 23:599-606.
10. Blaney J M, Dietrich S W, Reynolds M A, Hansch C (1979) Quantitative structure-activity relationship of 5-(X-benzyl)-2,4-diaminopyrimidines inhibiting bovine liver dihydrofolate reductase. J Med Chem 22:614-617.
11. Hopfinger A J (1980) A QSAR investigation of dihydrofolate reductase inhibition by Baker triazines based upon molecular shape analysis. J Am Chem Soc 102:7196-7206.
12. Cramer III R D Paterson D E, Bunce J D (1988) Comparative molecular-field analysis (CoMFA) .1. effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110:5959.
13. Klebe G, Abraham Ute, Mietzner Thomas (1994) Molecular Similarity Indices in a Comparative Analysis (CoMSIA) of Drug Molecules to Correlate and Predict Their Biological Activity. J Med Chem 37:4130-4146.
14. Aoyama T, Suzuki Y, Ichikawa H (1990) Neural Networks Applied to Quantitative Structure-Activity Relationship Analysis. J Med Chem 33 :2583-2590.
15. Oinuma H, Miyake K Yamanaka M, Nomoto K, Katoh H, Sawada K, Shino M, Hamano S (1989) Neural Networks Applied to Structure-Activity Relationships. J Med Chem 33:905-908.
16. Vapnik V (2000) The nature of statistical learning theory. Springer Verlag.
17. Holland J H (1975) Adaptation in Natural and Artificial System. The University of Michigan Press, Ann Arbor, MI.
18. Rogers D, Hopfinger A J (1994) Application of genetic function approxiamation to quantitative structure-activity-relationships and quantitative structure-property relationships. J Chem Inf Comput Sci 34:854.
19. Kubinyi H (1994) Variable Selection in QSAR Studies. I. An Evolutionary Algorithm. Quant Struct-Act Rel 13:285-294.
20. Kubinyi H (1994) Variable Selection in QSAR Studies. II. A Highly Efficient Combination of Systematic Search and Evolution. Quant Struct-Act Rel 13:393-401.
21. Kawakami Y, Inoue A, Kawai T, et al.The Rationale for E2020 as a Potent Acetylcholinesterase Inhibitor [J]. Bioorg Med Chem, 1996, 4:1429.
22. Martin Y C, Lin C T, Wu J. Application of CoMFA to D1 Dopaminergic Agonists: A Case Study. In: Kubinyi H, ed. 3D-QSAR in Drug Design: Theory, Methods and Applications [M]. Leiden: ESCOM Science Publishers, 1993, 643.
23. Koshland D J (1958) Application of a theory of enzyme specificity to protein synthesis. Proc Natl Acad Sci 44:98.
24. Jiang F, Kim S H (1991) Soft docking-matching of molecular surface cubes. J Mol Biol 219:79-102.
25. Goodsell D S, Olson A J (1990) Automated docking of substrates to proteins by simulated annealing. Proteins: Str Func and Genet 8:195.
26. Kuntz I D (1992) Structure-based strategies for drug design and discovery. Science 257:1078.
27. Goodsell D S, Morris G M, Olson A J (1996) Automated docking of flexible ligands: applications of AutoDock. J Mol Recognition 9:1.
28. Morris G M, Goodsell D S, Huey R, Olson A J (1996) Distributed automated docking of flexible ligands to proteins: parallel applications of Autodock 2.4. J Comput-Aid Mol Des 10:293.
29. Morris G M, Goodsell D S, Halliday R S, Huey R, Hart W E, Belew R K, Olson A J (1998) Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639.
30. Rao M S, Olson A J (1999) Modelling of Factor Xa-inhibitor complexes: a computational flexible docking approach. Proteins 34:173.
31. Osterberg F, Morris G M, Sanner M F, Olson A J, Goodsell D S (2002) Automated docking to multiple targer structures: Incorporation of protein mobility and structural water heterogeneity in AutoDock. Proteins 46:34.
32. Gschwend D A, Sirawaraporn W, Santi D V, Kuntz I D (1997) Specificity in structure-based drug design: Identification of a novel, selective inhibitor of Pneumocystis carinii dihydrofolate reductase. Protein 29:59.
33. Schoichet B K, Stroud R M, Santi D V, Kuntz I D, Perry K M (1993) Structure-based discovery of thymidylate synthase. Science 259:1445.
34. Asperger O, Kleber H P (1991) Distribution and diversity of bacterial Cytochromes P450. Taylor and Francis, London 1-53.
35.许华夏等(2002)生物细胞色素P450的研究进展.农业环境保护21:188-191.
36. Frear D S, Suwanson H R, Tanaka F S (1969) N-Demethylation of substituted 3-(phenyl)-1-methylureas: isolation and characterization of a microsomal mixed function oxidase from cotton. Phytochemistry 8:2157.
37. Gonzalez F J, Mackenzie P I, Kimura S, Nebert D W (1984) Isolation and characterization of mouse full-length cDNA and genomic clones of 3-methylcholanthrene-inducible cytochrome P1-450 and P3-450. Gene 29:281-292.
38. Nebert D W, Gonzalez F J (1987) P450 genes: structure, evolution and regulation. Annu Rev Biochem 56:945-993.
39. Omura T, Ishimura Y, Fujii K Y (1993) Cytochrome P450 2: Peroxidative reactions of diversozymes. FASEB J 10 :428.
40. Anandatheerthavarada H K, Vijayasarathy C, Bhagwat S V, Miswas G, Mullick J, Avadhani N G (1999) Physiological role of the N-terminal processed P4501A1 targeted to mitochrondria in erythromycin metabolism and reversal of erythromycin-mediated inhibition of mitochondrial protein synthesis. J Biol Chem 274:6617-6625.
41. Daly A K, Brockmoller J, Broly F (1996) Nomenclature for human CYP2D6 alleles. Pharmacogenetics 6:193-201.
42. Johansson I, Lundqvist E, Bertilsson L, Dahl M L, Sjoqvist F, Ingelman-Sundberg M (1993) Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 90:11825-11829.
43. Nebert D W, Russell D W (2002) Clinical importance of the cytochromes P450. Lancet360:1155-1162.
44. Guengerich F P (2003) Cytochromes P450, drugs and diseases. Molecular interventions 3:194:204.
45. Nelson D R (2003) Comparison of P450s from human and fugu: 420 million years of vertebrate P450 evolution. Arch Biochem Biophys 409:18-24.
46. Nelson D R, Schuler M A, Paquette S M (2004) Comparative Genomics of Rice and Arabidopsis: Analysis of 727 Cytochrome P450 Genes and Pseudogenes from a Monocot and a Dicot. Plant Physiology 135:756.
47. Gonzale F, Idle J R (1993) Pharmacogene phenotyping and genotyping. Present status and future potential. Pharmacol Therp 53:410.
48.周园等(2002)细胞色素P450酶的研究进展农垦医学24:224-226.
49. Carrier F, Chang CY, Duh J L (1994) Interaction of the regulatory domains of murine Cyplal gene with two DNA-binding proteins in addition to the Ah receptor and the Ah receptor nuclear translocatot (ARNT). Biochem Pharmacol 48:1767-1778.
50. Rendic S. Di Carlo F J (1997) Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 29:413-580.
51. Lewis D, Watson E, Lake B G (1998) Evolution of the cytochrome P450 superfamily: sequence alignments and pharmacokinetics. Mutat Res 410:245-270.
52. Marichal P, Koymans L, Williemsens S (1999) Contribution of mutations in the cytochrome P450 14α-demethylase to azole resistance in Candida albicans. Microbiology 145:2701-2713.
53. Guengerich F P (2003) Human cytochrome P450 enzymes. In Cytochrome P450, 3rd Edn, Plenum Press, New York.
54. Brodie A M H (1985) Aromatase inhibition and its pharmacologic implications. Biochem Pharmacol 34:3213-3219.
55. Nakamura K, Goto F, Ray W A, McAllister, C B, Jacqz E, Wilkinson G R, Branch R A (1985) Interethnic difference in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther
38:402-408.
56. Mahgoub A, Idle J R, Dring L G, Lancaster R, Smith R L (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet ii:584-586.
57. Smith R L (1988) The role of metabolism and disposition studies in the safety assessment of pharmaceuticals. Xenobiotica 18:89-96.
58. Chou W H, Yan F X, de Leon J (2000) Extension of a pilot study : Impact from the cytochrome P450 2D6 polymorphism on outcome and costs associated with severe mental illness. J Clin Psychopharmacol 20:246-251.
59. Ieiri I, Kubota T, Urae A (1996) Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4, in Japanese subjects. Clin Pharmacol Ther 59:647-653.
60. Kawabata H, Habu Y, Tomioka H (2003) Effect of different proton pump inhibitors, differences in CYP2C19 genotype and antibiotic resistance on the eradication rate of Helicobacter pylori infection by a 1-week regimen of proton pump inhibitor, amoxicillin and clarithromycin. Aliment Pharmacol Therap 17:259-264.
61. Kivisto K T, Neuvone P J, Klotz U (1994) Inhibition of terfenadine metabolism :Pharmacokinetic and pharmacodynamic consequences. Clin Pharmacokinet 27:1-5.
62. Janz D, Schmidt D (1974) Antiepileptic drugs and failure of oral contrceptives. Lancet i:1113.
63. Bolt H M, Kappus H, Bolt M (1975) Effect of rifampicin treatment on the metabolism of oestradiol and 17α-ethinyloestradiol by human liver microsomes. Eur J Clin Pharmacol 8:301-307.
64. Evans W E, Relling M V (1999) Pharmacogenomics: Translatin function genomics into rational therapeutics. Science 286:487-491.
65. Sarkar P K, Ahluwalia G, Vijayan V K, Talwar A (2009) Critical care aspects of malaria J Intensive Care Med 1-11.
66. Roepe P D (2009) The molecular and physiologic basis of quinoline drug resistance in P. falciparum malaria. Future microbiol 4:441-455.
67. Breman J G (2001) The ears of the hippopotamus: manifestations, determinants, estimates of the malaria burden. Am J Trop Med Hyg 64:1-11.
68.曲莉,钱锋疟疾疫苗研究进展. Foreign Med Sci Parasit Dis 32:147-152.
69. Carter R (2001) Transmission blocking malaria vaccines. Vaccine 19:2309-2315.
70. Glyde D F (1990) Immunity to Plasmodium falciparum and vivax malaria induced by irradiated sporozoites: a review of the university of Maryland studies. Bull WHO 68:9-12.
71. Sedegah M, Hedstrom R, Hobart P (1994) Protection against malaria by immunization with plasmid DNA encoding circumsporozoite protein. 91:9866-9870.
72. Malaria Vaccine Technology Roadmap http://www.malariavaccineroadmap.net.
73. Hyde J E (2005) Drug-resist malaria. Trends Parasitol 21:494-498.
74. Ambroise-Thomas P, Rossignol J F (1986) Chemotherapy of resistant falciparum malaria. Parasitol 2:79-80.
75. Wongsrichanalai C (2002) Epidemiology of drug-resistant malaria. Lancet Infect Dis 2:209-218.
76. Mackinnon M J, Gandon S, Read A F (2008) Virulence evolution in response to vaccination: The case of malaria. Vaccine 26:42-52.
1. Rendic S (2002) Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev 34:83-448. Doi:10.1081/DMR-120001392.
2. Ekins S, Bravi G., Binkley S, Gillespie J, Ring B, Wikel J, Wrighton S (1999) J Pharmacol Exp Ther 290:429-438.
3. Kremers P (2002) Can Drug-Drug Interactions Be Predicted from In Vitro Studies? ScientificWorldJournal 2:751-766. Doi:10.1100/tsw.2002.144
4. Domanski T, He Y, Khan K, Roussel F, Wang Q, Halpert J (2001) Phenylalanine and Tryptophan Scanning Mutagenesis of CYP3A4 Substrate Recognition Site Residues and Effect on Substrate Oxidation and Cooperativity Biochemistry 40:10150-10160. Doi: 10.1021/bi010758a.
5. Ekins S, Stresser D, Williams JA (2001) In vitro and pharmacophore insights into CYP3A enzymes. Trends Pharmacol Sci 24:161-166. Doi:10.1016/S0165-6147(03)00049-X.
6. Iannella N, Back A (2001) A spiking neural network architecture for nonlinear function approximation. Neural Netw 14:933-939. Doi:10.1016/S0893-6080(01)00080-6.
7. Pomerleau D (1993) Neural network perception for mobile robot guidance. Kluwer Academic Publishers Norwell, MA, USA.
8. Tetteh J, Suzuki T, Metcalfe E, Howells S (1999) Quantitative Structure Property Relationships for the Estimation of Boiling Point and Flash Point Using a Radial Basis Function Neural Network. J Chem Inf Comput Sci 39:491-507. Doi:10.1021/ci980026y
9. Xiang Y, Liu M, Zhang X, Zhang R, Hu Z, Fan B, Doucet J, Panaye A (2002) Quantitative prediction of liquid chromatography retention of N-benzylideneanilines based on quantum chemical parameters and radial basis function neural network. J Chem Inf Comput Sci 42 :592-597. Doi:10.1021/ci010067l.
10. Yeun Y, Lee K, Yang Y (1999) Function approximations by coupling neural networks and genetic programming trees with oblique decision trees. Artif Intell Eng 13:223-239. Doi:10.1016/S0954-1810(98)00015-6.
11. Boser B, Guyon I, Vapnik V (1992) A training algorithm for optimal margin classifiers. ACM New York, NY, USA 144-152.
12. Burges C (1998) A tutorial on support vector machines for pattern recognition. Data Min Knowl Discov 2:121-167.
13. Sch?lkopf B, Smola A (2002) Learning with kernels. Citeseer.
14. Vapnik V (2000) The nature of statistical learning theory. Springer Verlag.
15. Müller K, Mika S, R?tsch G., Tsuda K, Sch?lkopf B (2001) An introduction to kernel-based learning algorithms. IEEE Trans Neural Netw 12:181-201.
16. Burbidge R, Trotter M, Buxton B, Holden S (2001) Drug design by machine learning: support vector machines for pharmaceutical data analysis. Comput Chem 26:5-14. Doi:10.1016/S0097-8485(01)00094-8.
17. Liu H, Zhang R, Luan F, Yao X, Liu M, Hu Z, Fan B (2003) Diagnosing breast cancer based on support vector machines. J Chem Inf Comput Sci 43:900-907.
18. R?tsch G, Demiriz A, Bennett K (2002) Sparse regression ensembles in infinite and finite hypothesis spaces. Mach Learn 48:189-218.
19. Weston J, Pérez-Cruz F, Bousquet O, Chapelle O, Elisseeff A, Sch?lkopf B (2003) Feature selection and transduction for prediction of molecular bioactivity for drug design. Oxford Univ Press 19:764-771.
20. Arimoto R, Prasad M, Gifford E (2005) Development of CYP3A4 inhibition models: comparisons of machine-learning techniques and molecular descriptors. J Biomol Screen 10:197. Doi: 10.1177/1087057104274091.
21. Yap C, Chen Y (2005) Prediction of cytochrome P450 3A4, 2D6, and 2C9 inhibitors and substrates by using support vector machines. J Chem Inf Model 45 :982-992. Doi: 10.1021/ci0500536.
22. Terfloth L, Bienfait B, Gasteiger J (2007) Ligand-based models for the isoform specificity of cytochrome P450 3A4, 2D6, and 2C9 substrates. J Chem Inf Model 47:1688-1701. Doi: 10.1021/ci700010t.
23. Leong M, Chen T (2008) Prediction of cytochrome P450 2B6-substrate interactions using pharmacophore ensemble/support vector machine (PhE/SVM) approach. Med Chem 4:396-406.
24. Leong M, Chen Y, Chen, H, Chen P (2008) Development of a new predictive model for interactions with human cytochrome P450 2A6 using Pharmacophore Ensemble/Support Vector Machine (PhE/SVM) approach. Pharmaceutical Research 987-1000.
25. Vasanthanathan P, Taboureau O, Oostenbrink C, Vermeulen N, Olsen L, Jorgensen F (2009) Classification of cytochrome P450 1A2 inhibitors and noninhibitors by machine learning techniques. Drug Metab Dispos 37:658.
26. Kriegl J, Arnhold T, Beck B, Fox T (2005) A support vector machine approach to classify human cytochrome P450 3A4 inhibitors. J Comput Aided Mol Des 19:189-201. Doi:10.1007/s10822-005-3785-3.
27. Kriegl J, Arnhold T, Beck B, Fox T (2005) Prediction of human cytochrome P450 inhibition using support vector machines. QSAR Comb Sci 24:491-502. Doi: 10.1002/qsar.200430925.
28. Stresser D, Blanchard A, Turner S, Erve J, Dandeneau A, Miller V, Crespi C (2000) Substrate-dependent modulation of CYP3A4 catalytic activity: analysis of 27 test compounds with four fluorometric substrates. Drug Metab Dispos 28:1440.
29. Wanchana S, Yamashita F, Hashida M (2003) QSAR analysis of the inhibition of recombinant CYP 3A4 activity by structurally diverse compounds using a genetic algorithm-combined partial least squares method. Pharm Res 20:1401-1408.
30. Toutios A, Margaritis K (2005) Mapping between the speech signal and articulatory trajectories. Proceedings of the 7th HERCMA.
31. Unger S, Hansch C (1973) On Model Building in Structure–Activity Relationships. A Reexamination of Adrenergic Blocking Activity of–halo––arilalkylamines. J Med Chem 16:745–749.
32. Chang C, Lin C (2001) LIBSVM: a library for support vector machines.
33. Oprea T (2000) Property distribution of drug-related chemical databases. J Comput Aided Mol Des 14:251-264.
34. Lipinski C, Lombardo F, Dominy B, Feeney P (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3-25. Doi:10.1016/S0169-409X(96)00423-1.
35. Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity—arapid access to atomic charges. Tetrahedron 36:3219-3228. Doi:10.1016/0040-4020(80)80168-2.
36. Appiah-Opong R, de Esch I, Commandeur J, Andarini M, Vermeulen N (2008) Structure–activity relationships for the inhibition of recombinant human cytochromes P450 by curcumin analogues. Eur J Med Chem 43:1621-1631. Doi:10.1016/j.ejmech.2007.10.034.
37. Petitjean M (2002) Applications of the radius-diameter diagram to the classification of topological and geometrical shapes of chemical compounds. J Chem Inf Comput Sci 32:331-337.
38. Hall L, Kier L (1991) The molecular connectivity chi indexes and kappa shape indexes in structure-property modeling. Rev Comp Ch 2:367.
1. Shimada T, Watanabe J, Inoue K, Guengerich F P, Gillam E M J (2001) Specificity of 17β-oestradiol and benzo(a)pyrene oxidation by polymorphic human cytochrome P4501B1 variants substituted at residues 48, 119 and 432. Xenobiotica 31:163-176.
2. Shimada T, Oda Y, Gillam E M J, Guengerich F P, Inoue K (2001) Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P450 1B1 allelic variants and other human cytochromes P450 in Salmonella tryphimurium NM2009. Drug Metabolism and Disposition 29:1176-1182.
3. Born S L, Caudill D, Fliter K L, Purdon M P (2002) Identification of the cytochromes P450 that catalyze coumarin 3,4-epoxidation and 3-hydroxylation. Drug Metabolism and Disposition 30:483-487.
4. Chua M.-S, Kashiyama E, Bradshaw T D, Stinson S F, Brantley E, Sausville E A, Stevens M F G (2000) Role of CYP1A1 in modulation of antitumor properties of the novel agent
2-(4-amino-3-methylphenyl)benzothiazole (DF203, NSC674495) in human breast cancer cells. Cancer Research 60:5196-5203.
5. Schwarz D, Kisselev P, Schunck W-H, Chernogolov A, Boidol W, Cascorbi I, Roots I (2000) Allelic variants of human cytochrome P450 1A1 (CYP1A1): effect of T461N and I462V substitions on steroid hydroxylase specificity. Pharmacogenetics 10:519-530。
6. Rochat R, Morsman J M, Murray G I, Figg W D, McLeod H L (2001) Human CYP1B1 and anticancer agent metabolism: mechanism for tumor-specific drug inactivation? Journal of Pharmacology and Experimental Therapeutics 296:537-541.
7. Murray M, Reidy G F (1990) Selectivity in the inhibition of mammalian cytochromes P450 by chemical agents. Pharmacological Reviews 42:85-101.
8. Liu J, Ericksen S S, Besspiata D, Fisher C W, Szklarz G D (2003) Characterization of substrate binding to cytochrome P450 1A1 using molecular modelling and kinetic analysis: case of residue 382. Drug Metabolism and Disposition 31:412-420.
9. Ching M S, Blake C L, Malek N A, Angus P W, Ghabrial H (2001) Differential inhibition of human CYP1A1 and CYP1A2 by quinidine and quinine. Xenobiotica 31:757-767.
10. Potter G A, Patterson L H, Wanogho E, Perry P J, Butler P C, Ijaz T, Ruparelia K C, Lamb J H, Farmer P B, Stanley L A, Burke M D (2002) The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1. British Journal of Cancer 86:774-778.
11. Zhang Z, Fasco M J, Huang Z, Guengerich F P, Kaminsky L S (1995) Human cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. Drug Metabolism and Disposition 23:1339-1345.
12. Gallagher E P, Kunze K L, Stapleton P L, Eaton D L (1996) The kinetics of aflatoxin B1 oxidation by human cDNA-expressed and human liver microsomal cytochromes P4501A2 and 3A4. Toxicology and Applied Pharmacology 141:595-606.
13. Hammons G J, Milton D, Stepps K, Guengerich F P, Tukey R H, Kadlubar F F (1997) Metabolism of carcinogenic heterocyclic and aromatic amines by recombinant human cytochrome P450 enzymes. Carcinogenesis 18:851-854.
14. Tassaneeyakul W, Mohamed Z, Birkett D J, McManus M E, Veronese M E, Tukey R H,Quattrochi L C, Gonzalez F J, Miners J O (1992) Caffeine as a probe for human cytochromes P450: validation using cDNA expression, immunoinhibition and microsomal kinetic and inhibitor techniques. Pharmacogenetics 2:173-183.
15. Tassaneeyakul W, Birkett D J, Edwards J W, Veronese M E, Tassaneeyakul W, Tukey R H, Miners J O (1996) Human cytochrome P450 isoform specificity in the regioselective metabolism of toluene and o-, m- and p-xylene. Journal of Pharmacology and Experimental Therapeutics 273:101-108.
16. Yamazaki H, Shaw P M, Guengerich F P, Shimada T (1998) Roles of cytochrome P450 1A2 and 3A4 in the oxidation of estradiol and estrone in human liver microsomes. Chemical Research in Toxicology 11:659-665.
17. Parikh A, Josephy P D, Guengerich F P (1999) Selection and characterization of human cytochrome P4501A2 mutants with altered catalytic properties. Biochemistry 38:5283-5289.
18. Guengerich F P (1999) Inhibition of oral contraceptive steroid-metabolizing enzymes by steroids and drugs. American Journal of Obstetrics and Gynecology 163:2159-2163.
19. FaccioláG, Midestrand M, von Baher C, Tybring G (2001) Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. European Journal of Clinical Pharmacology 56:881-888.
20. Ayivor S W, Baird J, Pritchard M P (2002) Recombinant human CYP1A2 catalyzes the O-demethylation of 7-methoxycoumarin. Drug Metabolism Reviews 34:Supplement 1, 46.
21. Turesky R J, Constable A, Richoz J, Varga N, Markovic J, Martin M V, Guengerich F P (1998) Activation of heterocyclic aromatic amines by rat and human liver microsomes and by purified rat and human cytochrome P4501A2. Chemical Research in Toxicology 11:925-936.
22. Rodrigues A D (1999) Integrated cytochrome P450 reaction phenotyping: attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes. Biochemical Pharmacology 57:465-480.
23. Zhao K, Murray S, Davies D S, Boobis A R, Gooderham N J (1994) Metabolism of the food derived mutagen and carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine (PhIP) by human liver microsomes. Carcinogenesis 15:1285-1288.
24. Becquemont L, Le Bot M A, Riche C, Funck-Brentano C, Jaillon P, Beaune P (1998) Use of heterologously expressed human cytochrome P4501A2 to predict tacrine-fluvoxamine drug interaction in man. Pharmacogenetics 8:101-108.
25. Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A, Raunio H (1998) Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica 28:1203-1253.
26. Le Gal A, Dreano Y, Lucas D, Berthou F (2003) Diversity of selective environmental substrates for human cytochrome P450 2A6: alkoxyethers, nicotine, coumarin, N-nitrosodiethylamine and N-nitrosobenzylmethylamine. Toxicology Letters 144:77-91.
27. Nakajima, M., Tamamoto, T., Nunoya, K.-I., Yokoi, T., Nagashima, K., Inoue, K., Funae, Y., Shimada N, Kamataki T, Kuroiwa Y (1996) Characterization of CYP2A6 involved in 3'-hydroxylation of cotinine in human liver microsomes. Journal of Pharmacology and Experimental Therapeutics 277:1010-1015.
28. Walter B A, Hundal J S (1994) In vitro metabolism of fadrozole (CGS16949A) in human microsomes and human cell lines expressing a single P450 isozyme. 6th North American ISSX Meeting, Volume 6, Raleigh, North Carolina, p.187.
29. Gillam E M J, Notley L M, Cai H, De Voss J J, Guengerich F P (2000) Oxidation of indole bycytochrome P450 enzymes. Biochemistry 39:13817-13824.
30. Messina E S, Tyndale R F, Sellers E M (1997) A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes, Journal of Pharmacology and Experimental Therapeutics 282:1608-1614.
31. Jones B C, Tyman C A, Smith D A (1997) Identification of the cytochrome P450 isoforms involved in O-demethylation of 4-nitroanisole in human liver microsomes. Xenobiotica 27:1025-1037.
32. Su T, Bao Z, Zhang Q-Y, Smith T J, Hong J-Y, Ding X (2000) Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Research 60:5074-5079.
33. Reigh G, McMahon H, Ishizaki M, Ohara T, Shimane K, Esumi Y, Green C, Tyson C, Ninomiya S-I (1996) Cytochrome P450 species involved in the metabolism of quinoline. Carcinogenesis 17:1989-1996.
34. Nunoya K-I, Yokoi Y, Kimura K, Kodama T, Funayama M, Inoue K, Nagashima K, Funae Y, Shimada N, Green C, Kamataki T (1996) (+)-Cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502) as a novel substrate for cytochrome P4502A6 in human liver microsomes. Journal of Pharmacology and Experimental Therapeutics 277:768-774.
35. Komatsu T, Yamazaki H, Shimada N, Nakajima H, Yokoi T (2000) Roles of cytochromes P450 1A2, 2A6 and 2C8 in 5-fluorouracial formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metabolism and Disposition 28:1457-1463.
36. Ekins S, Bravi G, Ring B J, Gillespie T A, Gillespie J S, VandenBranden M, Wrighton S A, Wikel J H (1999) Three-dimensional quantitative structure activity relationship analyses of substrates for CYP2B6. Journal of Pharmacology and Experimental Therapeutics 288:21-29.
37. Ekins S, Wrighton S A (1999) The role of CYP2B6 in human xenobiotic metabolism. Drug Metabolism Reviews 31:719-754.
38. Ekins S, Ring B J, Hall S D, Wrighton S A (1998) Autoactivation and activation of the cytochrome P450s. International Journal of Clinical Pharmacology and Therapeutics 36:642-651.
39. Pearce R E, Vakkalagadda G R, Leeder J S (2002) Pathways of carbamazepine bioactivation in vitro 1. Characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites. Drug Metabolism and Disposition 30:1170-1179.
40. Huang Z, Roy P, Waxman D J (2000) Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochemical Pharmacology 59:961-972.
41. Hidestrand M, Oscarson M, Salonen J S, Nyman L, Pelkonen O, Turpeinen M, Ingelman-Sundberg M (2001) CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson's Disease, as revealed from experiments with recombinant enzymes. Drug Metabolism and Disposition 29:1480-1484.
42. Wang Q, Halpert J R (2002) Combined three-dimensional quantitative structure-activity relationship analysis of cytochrome P450 2B6 substrates and protein homology modeling. Drug Metabolism and Disposition 30:86-95.
43. Ohyama K, Nakajima M, Nakamura S, Shimada N, Yamazaki H, Yokoi T (2000) Asignificant role of human cytochrome P450 CYP2C8 in amiodarone N-deethylation: an approach to predict the contribution with relative activity factor. Drug Metabolism and Disposition 28:1303-1310.
44. Li X-Q, Bjorkman A, Andersson T B, Ridderstrom M, Masimirembwa C M (2002) Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. Journal of Pharmacology and Experimental Therapeutics 300:399-407.
45. Zeldin D C, Moomaw C R, Jesse N, Tomer K B, Beetham J, Hammock B D, Wu S (1996) Biochemical characterization of the human liver cytochrome P450 arachidonic acid epoxygenase pathway. Archives of Biochemistry and Biophysics 330:87-96.
46. Miller V P, Stresser D M, Blanchard A P, Turner S, Crespi C L (2000) Fluorometric high-throughput screening for inhibitors of cytochrome P450. Annals of the New York Academy of Sciences 919:26-32.
47. Mancy A, Antignac M, Minoletti C, Dijols S, Mouries V, Ha Duong N-T, Battioni P, Dansette P M, Mansuy D (1999) Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P4502Cs. Biochemistry 38:14264-14270.
48. Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck J-P, Robinson W T (1999) The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochorme P450 and implications for metabolic drug interactions. Drug Metabolism and Disposition 27:410-416.
49. Nadin L, Murray M (1999) Participation of CYP2C8 in retinoic acid 4-hydroxylation in human hepatic microsomes. Biochemical Pharmacology 58:1201-1208.
50. Leo M A, Lasker J M, Raucy J L, Kim C-I, Black M, Lieber C S (1989) Metabolism of retinol and retinoic acid by human liver cytochrome P450IIC8. Archives of Biochemistry and Biophysics 269:305-312.
51. Baldwin S J, Clarke S E, Chenery R J (1999) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. British Journal of Clinical Pharmacology 48:424-432.
52. Crespi C L, Chang T K H, Waxman D J (1998) High-performance liquid chromatographic analysis of CYP2C8-catalyzed paclitaxel 6α-hydroxylation, in: Cytochrome P450 Protocols (I.R. Phillips and E.A. Shephard, eds.) Humana Press, Totowa, New Jersey, 123-127.
53. Sahi J, Black C B, Hamilton G A, Zheng X, Jolley S, Rose K A, Gilbert D, Le Cluyse E L, Sinz M W (2003) Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metabolism and Disposition 31:439-446.
54. Bonnabry P, Leeman T, Dayer P (1994) Biotransformation by hepatic P450TB (CYP2C) controls mefenamic acid elimination. Clinical Pharmacology and Therapeutics 55:139.
55. Bonnabry P, Leeman T, Dayer P (1996) Role of human liver microsomal CYP2C9 in the biotransformation of lornoxicam. European Journal of Clinical Pharmacology 49:305-308.
56. Stearns R A, Chakravarty P K, Chen R, Lee Chiu S-H (1995) Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Drug Metabolism and Disposition 23:207-215.
57. Bajpai M, Roskos L K, Shen D D, Levy R H (1996) Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite.Drug Metabolism and Disposition 24:1401-1403.
58. Leeman T D, Transon C, Bonnabry P, Dayer P (1993) A major role for cytochrome P450TB (CYP2C subfamily) in the actions of non-steroidal anti-inflammatory drugs. Drugs Under Experimental Clinical Research 19:189-195.
59. Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosakawa M, Chiba K (2000) CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics 10:95-104.
60. Yamazaki H, Suzuki M, Tane K, Shimada N, Nakajima M, Yokoi T (2000) In Vitro inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human cytochrome P450 enzymes: comparison with pioglitazone and rosiglitazone. Xenobiotica 30:61-70.
61. McGinnity D F, Griffin S J, Moody G C, Voice M, Hanlon S, Freidberg T, Riley R J (1999) Rapid characterization of the major drug-metabolizing human hepatic cytochrome P450 enzymes expressed in Escherichia coli. Drug Metabolism and Disposition 27:1017-1023.
62. Knodell R G, Dubey R K, Wilkinson G R, Guengerich F P (1988) Oxidative metaboism of hexobarbital in human liver: relationship to polymorphic S-mephenytoin 4-hydroxylation, Journal of Pharmacology and Experimental Therapeutics 245:845-849.
63. Miyazawa M, Shindo M, Shimada T (2002) Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Drug Metabolism and Dispostion 30:603-607.
64. FaccioláG, Midestrand M, von Baher C, Tybring G. (2001) Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. European Journal of Clinical Pharmacology 56:881-888.
65. Tsao C-C, Wester M R, Ghanayem B, Coulter S J, Chanas B, Johnson E F, Goldstein J A (2001) Identification of human CYP2C19 residues that confer S-mephenytoin 4'-hydroxylase activity to CYP2C9. Biochemistry 40:1937-1944.
66. Kobayashi K, Kogo M, Tani M, Shimada N, Ishizaki T, Numazawa S, Yoshida T, Yamamoto T, Kuroiwa Y, Chiba K (2001) Role of CYP"C19 in stereoselective hydroxylation of mephobarbital by human liver microsomes. Drug Metabolism and Disposition 29:36-40.
67. Hoskins J, Shenfield G., Murray M, Gross A (2001) Characterization of moclobemide N-oxidation in human liver microsomes. Xenobiotica 31:387-397.
68. Andersson T, Miners J O, Veronese M E, Tassaneeyakul W, Tassaneeyakul W, Meyer U A, Birkett D J (1993) Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. British Journal of Clinical Pharmacology 36:521-530.
69. Birkett D J, Rees D, Andersson T, Gonzalez F J, Miners J O, Veronese M E (1994) In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylase. British Journal of Clinical Pharmacology 37:413-420.
70. VandenBranden M, Ring B J, Binkley S N, Wrighton S A (1996) Interaction of human liver cytochromes P450 in vitro with LY307640, a gastric proton pump inhibitor. Pharmacogenetics 6:81-91.
71. Wienkers L C, Wurden C J, Storch E, Kunze K L, Rettie A E, Trager W F (1996) Formation of (R)-8-hydroxywarfarin in human liver microsomes: a new metabolic marker for the (S)-mephenytoin hydroxylase P4502C19. Drug Metabolism and Disposition 24:610-614.
72. Kedderis G L, Batra R, Koop D R (1993) Epoxidation of acrylonitrile by rat and humancytochromes P450. Chemical Research in Toxicology 6:866-871.
73. BourriéM, Meunier V, Berger Y, Fabre G (1996) Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions catalyzed by human liver microsomes. Journal of Pharmacology and Experimental Therapeutics 277:321-332.
74. Nedelcheva V, Gut I, Soucek P, Tichavska B, Tynkova L, Mraz J, Guengerich F P, Ingelman-Sundberg M (1999) Metabolism of benzene in human liver microsomes: individual variations in relation to CYP2E1 expression. Archives of Toxicology 73:33-40.
75. Zhao G, Allis J W (2002) Kinetics of bromodichloromethane metabolism by cytochrome P450 isoenzymes in human liver microsomes. Chemico-Biological Interactions 140: 155-168.
76. Duescher R J, Elfarra A A (1994) Human liver microsomes are efficient catalysts of 1,3-butadiene oxidation: evidence for major roles by cytochromes P4502A6 and 2E1. Archives of Biochemistry and Biophysics 311:342-349.
77. Mitra A, Thummel K E, Kalhorn T F, Kharasch E D, Unadkat J D, Slattery J T (1995) Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo. Clinical Pharmacology and Therapeutics 58:556-566.
78. Bell L C, Guengerich F P (1997) Oxidation kinetics of ethanol by human cytochrome P450
2E1. Journal of Biological Chemistry 272:29643-29651.
79. Bachmann K, He Y, Sarver J G, Peng N (2003) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of ethosuximide by human hepatic microsomal enzymes. Xenobiotica 33:265-276.
80. Spracklin D K, Hankins D C, Fisher J M, Thummel K E, Kharasch E D (1997) Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro. Journal of Pharmacology and Experimental Therapeutics 281:400-411.
81. Bogaards J J P, Freidig A P, van Bladeren P J (2001) Prediction of isoprene diepoxide levels in vivo in mouse, rat and man using enzyme kinetic data in vitro and physiologically-based pharmacokinetic modelling. Chemico-Biological Interactions 138:247-265.
82. Clarke S E, Baldwin S J, Bloomer J C, Ayrton A D, Sozio R S, Chenery R J (1994) Lauric acid as a model substrate for the simultaneous determination of cytochrome P4502E1 and 4A in hepatic microsomes. Chemical Research in Toxicology 7:836-842.
83. Chen W, Koenigs L L, Thompson S J, Peter R M, Rettie A E, Trager W F, Nelson S D (1998) Oxidation of acetamidophen to its toxic quinone imine and nontoxic catechol by baculovirus-expressed and purified human cytochromes P4502E1 and 2A6. Chemical Research in Toxicology 11:295-301.
84. Carlson G P, Mantick N A, Powley M W (2000) Metabolism of styrene by human liver and lung. Journal of Toxicology and Environmental Health 59:591-595.
85. Dupont I, Berthou F, Bodenez P, Bardou L, Guirriec C, Stephan N, Dreano Y, Lucas D (1999) Involvement of cytochromes P450 2E1 and 3A4 in the 5-hydroxylation of salicylate in humans. Drug Metabolism and Disposition 27:322-326.
86.徐筱杰,等.计算机辅助药物分子设计.化学工业出版社,北京:2004.
87. Vapnik V (2000) The nature of statistical learning theory. Springer Verlag.
88. Toutios A, Margaritis K (2005) Mapping between the speech signal and articulatory trajectories. Proceedings of the 7th HERCMA
1. Bradshaw R A, Brickey W W, Walker K W (1998) N-Terminal processing: the methionine aminopeptidase and Nα-acetyl transferase families. Trends Biochem Sci 23:263–267.
2. Lowther W T, Matthews B W (2000) Structure and function of the methionine aminopeptidase. Biochim Biophys Acta 1477:157–167.
3. Wang J, Sheppard G S, Lou P, Kawai M, BaMaung N, Erickson S A, Tucker-Garcia L, Park C, Bouska J, Wang Y C, et al. (2003) Tumor Suppression by a Rationally Designed Reversible Inhibitor of Methionine Aminopeptidase-2 Cancer Res 63:7861–7869.
4. Bernier S G, Lazarus D D, Clark E, Doyle B, Labenski M T, Thompson C D, Westlin W F, Hannig G (2004) A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis. Proc Natl Acad Sci USA 101:10768–10773.
5. Vaughan M D, Sampson P B, Honek J F (2002) Methionine in and out of protein: targets for drug design. Curr Med Chem 9:385–409.
6. Zhang P, Nicholson D E, Bujnicki J M, Su X, Brendle J J, Ferdig M, Kyle D E, Milhous W K, Chiang P K (2002) Angiogenesis inhibitors specific for methionine aminopeptidase 2 as drugs for Malaria and Leishmaniasis. J Biomed Sci 9:34–40.
7. Cramer III R D Paterson D E, Bunce J D (1988) Comparative molecular-field analysis (CoMFA) .1. effect of shape on binding of steroids to carrier proteins. J Am Chem Soc
110:5959-5967.
8. Clark M, Cramer III R D (1993) The Probability of Chance Correlation Using Partial Least Squares (PLS). Quant Struct-Act Relat 12:137-145.
9. Klebe G, Abraham U, Mietzner T (1994) Molecular Similarity Indices in a Comparative Analysis (CoMSIA) of Drug Molecules to Correlate and Predict their Biological Activity. J Med Chem 37:4130-4146.
10. B?hm M, Stürzebecher J, Klebe G (1999) 3D QSAR Analyses using CoMFA and CoMSIA to Elucidate Selectivity Differences of Inhibitors Binding to Trypsin, Thrombin and Factor Xa. J Med Chem 42:458-477.
11. Stanton D T, Jurs P C (1990) Development and use of charged partial surface area descriptors in computer-assisted quantitative structure-property relationship studies. Anal Chem 62:2323-2329.
12. Clementi S, Cruciani G, Fifi P, Riganelli D, Valigi R, Musumarra G (1995) A new set of principal properties for heteroaromatics obtained by GRID. Quant Struct-Act Relat
15:108-120.
13. Goodford P J (1995) A computational procedure for determining energetically favourable binding sites on biologically important macromolecules. J Med Chem 28(7):849-857.
14. Pommier Y, Jaxel C, Heise C R, et al. SAR of topoisomeraseⅠinhibition by camptothecin derivatives: evidence for the existence of a ternary complex. In: Potmesil M, Kohn KW, ed. DNA topoisomerase in cancer. Oxford Univ Press, New York: 1991:121-132.
15. Vapnik V (2000) The nature of statistical learning theory. Springer Verlag.
16. Toutios A, Margaritis K (2005) Mapping between the speech signal and articulatory trajectories. Proceedings of the 7th HERCMA.
17. Schwede T, Kopp J, Guex N, Peitsch M C (2003) SWISS-MODEL: an automated proteinhomology-modelling server. Nucleic Acids Res, 31:3381-3385.
18. Stahle L, Wold S, Ellis G P, West G B (1988) Progress in Medicinal Chemistry. Elsevier, Amsterdam, The Netherlands 1988, 292–338.
19. Klebe G, Abraham U (1999) Comparative Molecular Similarity Index Analysis (CoMSIA) to Study Hydrogen Bonding Properties and to Score CombinatorialLibraries. J Comput Aided Mol Des 13:1-10.
20. Hall L H, Kier L B (1991) The Molecular Connectivity Chi Indices and Kappa Shape Indices in Structure-Property Modeling. Reviews of Computational Chemistry. 2.
21. Chang C, Lin C (2001) LIBSVM: a library for support vector machines.
2. Hansch C, Muir R.C, Fujita T, Maloney P, Geiger F, Streich M (1963) The correlation of Biological Activity of Plant Growth Regulators and Chlormycetin Derivatives with Hammett Constants and Partition Coefficients. J Am Chem Soc 85:2817-2824.
3. Hansch C, Fujita T (1963)ρ-σ-πAnalysisA Method for the Correlation of Biological Activity and Chemical Structure. J Am Chem Soc 86:1616-1626.
4. Muir R, Fujita T, Hansch C (1967) Structure-Activity Relationship in the Auxin Activity of Mono-Substituted Phenylacetic Acids. Plant Physiol. 42:1519-1526.
5. Kubinyi H (1976) Quantitative Structure-Activity Relationships. 7. The Bilinear Model, a New Model for Nonlinear Dependence of Biological Activity on Hydrophobic Character. JMed Chem 20:625-629.
6. Free S H, Wilson J W (1964) A Mathematical Contribution to Structure-Activity Studies. J Med Chem 7:395-399.
7. Kubinyi H, Kehrhahn O H (1976) Quantitative Structure-Activity Relationships. 2. A Mixed Approach, Based on Hansch and Free-Wilson Analysis. J Med Chem 19:587-600.
8. Crippen G M (1979) Distance geometry approach to rationalizing binding data. J Med Chem 22:988-997.
9. Crippen G M (1980) Quantitative structure-activity relationships by distance geometry: systematic analysis of dihydrofolate reductase inhibitors. J Med Chem 23:599-606.
10. Blaney J M, Dietrich S W, Reynolds M A, Hansch C (1979) Quantitative structure-activity relationship of 5-(X-benzyl)-2,4-diaminopyrimidines inhibiting bovine liver dihydrofolate reductase. J Med Chem 22:614-617.
11. Hopfinger A J (1980) A QSAR investigation of dihydrofolate reductase inhibition by Baker triazines based upon molecular shape analysis. J Am Chem Soc 102:7196-7206.
12. Cramer III R D Paterson D E, Bunce J D (1988) Comparative molecular-field analysis (CoMFA) .1. effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110:5959.
13. Klebe G, Abraham Ute, Mietzner Thomas (1994) Molecular Similarity Indices in a Comparative Analysis (CoMSIA) of Drug Molecules to Correlate and Predict Their Biological Activity. J Med Chem 37:4130-4146.
14. Aoyama T, Suzuki Y, Ichikawa H (1990) Neural Networks Applied to Quantitative Structure-Activity Relationship Analysis. J Med Chem 33 :2583-2590.
15. Oinuma H, Miyake K Yamanaka M, Nomoto K, Katoh H, Sawada K, Shino M, Hamano S (1989) Neural Networks Applied to Structure-Activity Relationships. J Med Chem 33:905-908.
16. Vapnik V (2000) The nature of statistical learning theory. Springer Verlag.
17. Holland J H (1975) Adaptation in Natural and Artificial System. The University of Michigan Press, Ann Arbor, MI.
18. Rogers D, Hopfinger A J (1994) Application of genetic function approxiamation to quantitative structure-activity-relationships and quantitative structure-property relationships. J Chem Inf Comput Sci 34:854.
19. Kubinyi H (1994) Variable Selection in QSAR Studies. I. An Evolutionary Algorithm. Quant Struct-Act Rel 13:285-294.
20. Kubinyi H (1994) Variable Selection in QSAR Studies. II. A Highly Efficient Combination of Systematic Search and Evolution. Quant Struct-Act Rel 13:393-401.
21. Kawakami Y, Inoue A, Kawai T, et al.The Rationale for E2020 as a Potent Acetylcholinesterase Inhibitor [J]. Bioorg Med Chem, 1996, 4:1429.
22. Martin Y C, Lin C T, Wu J. Application of CoMFA to D1 Dopaminergic Agonists: A Case Study. In: Kubinyi H, ed. 3D-QSAR in Drug Design: Theory, Methods and Applications [M]. Leiden: ESCOM Science Publishers, 1993, 643.
23. Koshland D J (1958) Application of a theory of enzyme specificity to protein synthesis. Proc Natl Acad Sci 44:98.
24. Jiang F, Kim S H (1991) Soft docking-matching of molecular surface cubes. J Mol Biol 219:79-102.
25. Goodsell D S, Olson A J (1990) Automated docking of substrates to proteins by simulated annealing. Proteins: Str Func and Genet 8:195.
26. Kuntz I D (1992) Structure-based strategies for drug design and discovery. Science 257:1078.
27. Goodsell D S, Morris G M, Olson A J (1996) Automated docking of flexible ligands: applications of AutoDock. J Mol Recognition 9:1.
28. Morris G M, Goodsell D S, Huey R, Olson A J (1996) Distributed automated docking of flexible ligands to proteins: parallel applications of Autodock 2.4. J Comput-Aid Mol Des 10:293.
29. Morris G M, Goodsell D S, Halliday R S, Huey R, Hart W E, Belew R K, Olson A J (1998) Automated docking using a lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639.
30. Rao M S, Olson A J (1999) Modelling of Factor Xa-inhibitor complexes: a computational flexible docking approach. Proteins 34:173.
31. Osterberg F, Morris G M, Sanner M F, Olson A J, Goodsell D S (2002) Automated docking to multiple targer structures: Incorporation of protein mobility and structural water heterogeneity in AutoDock. Proteins 46:34.
32. Gschwend D A, Sirawaraporn W, Santi D V, Kuntz I D (1997) Specificity in structure-based drug design: Identification of a novel, selective inhibitor of Pneumocystis carinii dihydrofolate reductase. Protein 29:59.
33. Schoichet B K, Stroud R M, Santi D V, Kuntz I D, Perry K M (1993) Structure-based discovery of thymidylate synthase. Science 259:1445.
34. Asperger O, Kleber H P (1991) Distribution and diversity of bacterial Cytochromes P450. Taylor and Francis, London 1-53.
35.许华夏等(2002)生物细胞色素P450的研究进展.农业环境保护21:188-191.
36. Frear D S, Suwanson H R, Tanaka F S (1969) N-Demethylation of substituted 3-(phenyl)-1-methylureas: isolation and characterization of a microsomal mixed function oxidase from cotton. Phytochemistry 8:2157.
37. Gonzalez F J, Mackenzie P I, Kimura S, Nebert D W (1984) Isolation and characterization of mouse full-length cDNA and genomic clones of 3-methylcholanthrene-inducible cytochrome P1-450 and P3-450. Gene 29:281-292.
38. Nebert D W, Gonzalez F J (1987) P450 genes: structure, evolution and regulation. Annu Rev Biochem 56:945-993.
39. Omura T, Ishimura Y, Fujii K Y (1993) Cytochrome P450 2: Peroxidative reactions of diversozymes. FASEB J 10 :428.
40. Anandatheerthavarada H K, Vijayasarathy C, Bhagwat S V, Miswas G, Mullick J, Avadhani N G (1999) Physiological role of the N-terminal processed P4501A1 targeted to mitochrondria in erythromycin metabolism and reversal of erythromycin-mediated inhibition of mitochondrial protein synthesis. J Biol Chem 274:6617-6625.
41. Daly A K, Brockmoller J, Broly F (1996) Nomenclature for human CYP2D6 alleles. Pharmacogenetics 6:193-201.
42. Johansson I, Lundqvist E, Bertilsson L, Dahl M L, Sjoqvist F, Ingelman-Sundberg M (1993) Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 90:11825-11829.
43. Nebert D W, Russell D W (2002) Clinical importance of the cytochromes P450. Lancet360:1155-1162.
44. Guengerich F P (2003) Cytochromes P450, drugs and diseases. Molecular interventions 3:194:204.
45. Nelson D R (2003) Comparison of P450s from human and fugu: 420 million years of vertebrate P450 evolution. Arch Biochem Biophys 409:18-24.
46. Nelson D R, Schuler M A, Paquette S M (2004) Comparative Genomics of Rice and Arabidopsis: Analysis of 727 Cytochrome P450 Genes and Pseudogenes from a Monocot and a Dicot. Plant Physiology 135:756.
47. Gonzale F, Idle J R (1993) Pharmacogene phenotyping and genotyping. Present status and future potential. Pharmacol Therp 53:410.
48.周园等(2002)细胞色素P450酶的研究进展农垦医学24:224-226.
49. Carrier F, Chang CY, Duh J L (1994) Interaction of the regulatory domains of murine Cyplal gene with two DNA-binding proteins in addition to the Ah receptor and the Ah receptor nuclear translocatot (ARNT). Biochem Pharmacol 48:1767-1778.
50. Rendic S. Di Carlo F J (1997) Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 29:413-580.
51. Lewis D, Watson E, Lake B G (1998) Evolution of the cytochrome P450 superfamily: sequence alignments and pharmacokinetics. Mutat Res 410:245-270.
52. Marichal P, Koymans L, Williemsens S (1999) Contribution of mutations in the cytochrome P450 14α-demethylase to azole resistance in Candida albicans. Microbiology 145:2701-2713.
53. Guengerich F P (2003) Human cytochrome P450 enzymes. In Cytochrome P450, 3rd Edn, Plenum Press, New York.
54. Brodie A M H (1985) Aromatase inhibition and its pharmacologic implications. Biochem Pharmacol 34:3213-3219.
55. Nakamura K, Goto F, Ray W A, McAllister, C B, Jacqz E, Wilkinson G R, Branch R A (1985) Interethnic difference in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther
38:402-408.
56. Mahgoub A, Idle J R, Dring L G, Lancaster R, Smith R L (1977) Polymorphic hydroxylation of debrisoquine in man. Lancet ii:584-586.
57. Smith R L (1988) The role of metabolism and disposition studies in the safety assessment of pharmaceuticals. Xenobiotica 18:89-96.
58. Chou W H, Yan F X, de Leon J (2000) Extension of a pilot study : Impact from the cytochrome P450 2D6 polymorphism on outcome and costs associated with severe mental illness. J Clin Psychopharmacol 20:246-251.
59. Ieiri I, Kubota T, Urae A (1996) Pharmacokinetics of omeprazole (a substrate of CYP2C19) and comparison with two mutant alleles CYP2C19m1 in exon 5 and CYP2C19m2 in exon 4, in Japanese subjects. Clin Pharmacol Ther 59:647-653.
60. Kawabata H, Habu Y, Tomioka H (2003) Effect of different proton pump inhibitors, differences in CYP2C19 genotype and antibiotic resistance on the eradication rate of Helicobacter pylori infection by a 1-week regimen of proton pump inhibitor, amoxicillin and clarithromycin. Aliment Pharmacol Therap 17:259-264.
61. Kivisto K T, Neuvone P J, Klotz U (1994) Inhibition of terfenadine metabolism :Pharmacokinetic and pharmacodynamic consequences. Clin Pharmacokinet 27:1-5.
62. Janz D, Schmidt D (1974) Antiepileptic drugs and failure of oral contrceptives. Lancet i:1113.
63. Bolt H M, Kappus H, Bolt M (1975) Effect of rifampicin treatment on the metabolism of oestradiol and 17α-ethinyloestradiol by human liver microsomes. Eur J Clin Pharmacol 8:301-307.
64. Evans W E, Relling M V (1999) Pharmacogenomics: Translatin function genomics into rational therapeutics. Science 286:487-491.
65. Sarkar P K, Ahluwalia G, Vijayan V K, Talwar A (2009) Critical care aspects of malaria J Intensive Care Med 1-11.
66. Roepe P D (2009) The molecular and physiologic basis of quinoline drug resistance in P. falciparum malaria. Future microbiol 4:441-455.
67. Breman J G (2001) The ears of the hippopotamus: manifestations, determinants, estimates of the malaria burden. Am J Trop Med Hyg 64:1-11.
68.曲莉,钱锋疟疾疫苗研究进展. Foreign Med Sci Parasit Dis 32:147-152.
69. Carter R (2001) Transmission blocking malaria vaccines. Vaccine 19:2309-2315.
70. Glyde D F (1990) Immunity to Plasmodium falciparum and vivax malaria induced by irradiated sporozoites: a review of the university of Maryland studies. Bull WHO 68:9-12.
71. Sedegah M, Hedstrom R, Hobart P (1994) Protection against malaria by immunization with plasmid DNA encoding circumsporozoite protein. 91:9866-9870.
72. Malaria Vaccine Technology Roadmap http://www.malariavaccineroadmap.net.
73. Hyde J E (2005) Drug-resist malaria. Trends Parasitol 21:494-498.
74. Ambroise-Thomas P, Rossignol J F (1986) Chemotherapy of resistant falciparum malaria. Parasitol 2:79-80.
75. Wongsrichanalai C (2002) Epidemiology of drug-resistant malaria. Lancet Infect Dis 2:209-218.
76. Mackinnon M J, Gandon S, Read A F (2008) Virulence evolution in response to vaccination: The case of malaria. Vaccine 26:42-52.
1. Rendic S (2002) Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev 34:83-448. Doi:10.1081/DMR-120001392.
2. Ekins S, Bravi G., Binkley S, Gillespie J, Ring B, Wikel J, Wrighton S (1999) J Pharmacol Exp Ther 290:429-438.
3. Kremers P (2002) Can Drug-Drug Interactions Be Predicted from In Vitro Studies? ScientificWorldJournal 2:751-766. Doi:10.1100/tsw.2002.144
4. Domanski T, He Y, Khan K, Roussel F, Wang Q, Halpert J (2001) Phenylalanine and Tryptophan Scanning Mutagenesis of CYP3A4 Substrate Recognition Site Residues and Effect on Substrate Oxidation and Cooperativity Biochemistry 40:10150-10160. Doi: 10.1021/bi010758a.
5. Ekins S, Stresser D, Williams JA (2001) In vitro and pharmacophore insights into CYP3A enzymes. Trends Pharmacol Sci 24:161-166. Doi:10.1016/S0165-6147(03)00049-X.
6. Iannella N, Back A (2001) A spiking neural network architecture for nonlinear function approximation. Neural Netw 14:933-939. Doi:10.1016/S0893-6080(01)00080-6.
7. Pomerleau D (1993) Neural network perception for mobile robot guidance. Kluwer Academic Publishers Norwell, MA, USA.
8. Tetteh J, Suzuki T, Metcalfe E, Howells S (1999) Quantitative Structure Property Relationships for the Estimation of Boiling Point and Flash Point Using a Radial Basis Function Neural Network. J Chem Inf Comput Sci 39:491-507. Doi:10.1021/ci980026y
9. Xiang Y, Liu M, Zhang X, Zhang R, Hu Z, Fan B, Doucet J, Panaye A (2002) Quantitative prediction of liquid chromatography retention of N-benzylideneanilines based on quantum chemical parameters and radial basis function neural network. J Chem Inf Comput Sci 42 :592-597. Doi:10.1021/ci010067l.
10. Yeun Y, Lee K, Yang Y (1999) Function approximations by coupling neural networks and genetic programming trees with oblique decision trees. Artif Intell Eng 13:223-239. Doi:10.1016/S0954-1810(98)00015-6.
11. Boser B, Guyon I, Vapnik V (1992) A training algorithm for optimal margin classifiers. ACM New York, NY, USA 144-152.
12. Burges C (1998) A tutorial on support vector machines for pattern recognition. Data Min Knowl Discov 2:121-167.
13. Sch?lkopf B, Smola A (2002) Learning with kernels. Citeseer.
14. Vapnik V (2000) The nature of statistical learning theory. Springer Verlag.
15. Müller K, Mika S, R?tsch G., Tsuda K, Sch?lkopf B (2001) An introduction to kernel-based learning algorithms. IEEE Trans Neural Netw 12:181-201.
16. Burbidge R, Trotter M, Buxton B, Holden S (2001) Drug design by machine learning: support vector machines for pharmaceutical data analysis. Comput Chem 26:5-14. Doi:10.1016/S0097-8485(01)00094-8.
17. Liu H, Zhang R, Luan F, Yao X, Liu M, Hu Z, Fan B (2003) Diagnosing breast cancer based on support vector machines. J Chem Inf Comput Sci 43:900-907.
18. R?tsch G, Demiriz A, Bennett K (2002) Sparse regression ensembles in infinite and finite hypothesis spaces. Mach Learn 48:189-218.
19. Weston J, Pérez-Cruz F, Bousquet O, Chapelle O, Elisseeff A, Sch?lkopf B (2003) Feature selection and transduction for prediction of molecular bioactivity for drug design. Oxford Univ Press 19:764-771.
20. Arimoto R, Prasad M, Gifford E (2005) Development of CYP3A4 inhibition models: comparisons of machine-learning techniques and molecular descriptors. J Biomol Screen 10:197. Doi: 10.1177/1087057104274091.
21. Yap C, Chen Y (2005) Prediction of cytochrome P450 3A4, 2D6, and 2C9 inhibitors and substrates by using support vector machines. J Chem Inf Model 45 :982-992. Doi: 10.1021/ci0500536.
22. Terfloth L, Bienfait B, Gasteiger J (2007) Ligand-based models for the isoform specificity of cytochrome P450 3A4, 2D6, and 2C9 substrates. J Chem Inf Model 47:1688-1701. Doi: 10.1021/ci700010t.
23. Leong M, Chen T (2008) Prediction of cytochrome P450 2B6-substrate interactions using pharmacophore ensemble/support vector machine (PhE/SVM) approach. Med Chem 4:396-406.
24. Leong M, Chen Y, Chen, H, Chen P (2008) Development of a new predictive model for interactions with human cytochrome P450 2A6 using Pharmacophore Ensemble/Support Vector Machine (PhE/SVM) approach. Pharmaceutical Research 987-1000.
25. Vasanthanathan P, Taboureau O, Oostenbrink C, Vermeulen N, Olsen L, Jorgensen F (2009) Classification of cytochrome P450 1A2 inhibitors and noninhibitors by machine learning techniques. Drug Metab Dispos 37:658.
26. Kriegl J, Arnhold T, Beck B, Fox T (2005) A support vector machine approach to classify human cytochrome P450 3A4 inhibitors. J Comput Aided Mol Des 19:189-201. Doi:10.1007/s10822-005-3785-3.
27. Kriegl J, Arnhold T, Beck B, Fox T (2005) Prediction of human cytochrome P450 inhibition using support vector machines. QSAR Comb Sci 24:491-502. Doi: 10.1002/qsar.200430925.
28. Stresser D, Blanchard A, Turner S, Erve J, Dandeneau A, Miller V, Crespi C (2000) Substrate-dependent modulation of CYP3A4 catalytic activity: analysis of 27 test compounds with four fluorometric substrates. Drug Metab Dispos 28:1440.
29. Wanchana S, Yamashita F, Hashida M (2003) QSAR analysis of the inhibition of recombinant CYP 3A4 activity by structurally diverse compounds using a genetic algorithm-combined partial least squares method. Pharm Res 20:1401-1408.
30. Toutios A, Margaritis K (2005) Mapping between the speech signal and articulatory trajectories. Proceedings of the 7th HERCMA.
31. Unger S, Hansch C (1973) On Model Building in Structure–Activity Relationships. A Reexamination of Adrenergic Blocking Activity of–halo––arilalkylamines. J Med Chem 16:745–749.
32. Chang C, Lin C (2001) LIBSVM: a library for support vector machines.
33. Oprea T (2000) Property distribution of drug-related chemical databases. J Comput Aided Mol Des 14:251-264.
34. Lipinski C, Lombardo F, Dominy B, Feeney P (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3-25. Doi:10.1016/S0169-409X(96)00423-1.
35. Gasteiger J, Marsili M (1980) Iterative partial equalization of orbital electronegativity—arapid access to atomic charges. Tetrahedron 36:3219-3228. Doi:10.1016/0040-4020(80)80168-2.
36. Appiah-Opong R, de Esch I, Commandeur J, Andarini M, Vermeulen N (2008) Structure–activity relationships for the inhibition of recombinant human cytochromes P450 by curcumin analogues. Eur J Med Chem 43:1621-1631. Doi:10.1016/j.ejmech.2007.10.034.
37. Petitjean M (2002) Applications of the radius-diameter diagram to the classification of topological and geometrical shapes of chemical compounds. J Chem Inf Comput Sci 32:331-337.
38. Hall L, Kier L (1991) The molecular connectivity chi indexes and kappa shape indexes in structure-property modeling. Rev Comp Ch 2:367.
1. Shimada T, Watanabe J, Inoue K, Guengerich F P, Gillam E M J (2001) Specificity of 17β-oestradiol and benzo(a)pyrene oxidation by polymorphic human cytochrome P4501B1 variants substituted at residues 48, 119 and 432. Xenobiotica 31:163-176.
2. Shimada T, Oda Y, Gillam E M J, Guengerich F P, Inoue K (2001) Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P450 1B1 allelic variants and other human cytochromes P450 in Salmonella tryphimurium NM2009. Drug Metabolism and Disposition 29:1176-1182.
3. Born S L, Caudill D, Fliter K L, Purdon M P (2002) Identification of the cytochromes P450 that catalyze coumarin 3,4-epoxidation and 3-hydroxylation. Drug Metabolism and Disposition 30:483-487.
4. Chua M.-S, Kashiyama E, Bradshaw T D, Stinson S F, Brantley E, Sausville E A, Stevens M F G (2000) Role of CYP1A1 in modulation of antitumor properties of the novel agent
2-(4-amino-3-methylphenyl)benzothiazole (DF203, NSC674495) in human breast cancer cells. Cancer Research 60:5196-5203.
5. Schwarz D, Kisselev P, Schunck W-H, Chernogolov A, Boidol W, Cascorbi I, Roots I (2000) Allelic variants of human cytochrome P450 1A1 (CYP1A1): effect of T461N and I462V substitions on steroid hydroxylase specificity. Pharmacogenetics 10:519-530。
6. Rochat R, Morsman J M, Murray G I, Figg W D, McLeod H L (2001) Human CYP1B1 and anticancer agent metabolism: mechanism for tumor-specific drug inactivation? Journal of Pharmacology and Experimental Therapeutics 296:537-541.
7. Murray M, Reidy G F (1990) Selectivity in the inhibition of mammalian cytochromes P450 by chemical agents. Pharmacological Reviews 42:85-101.
8. Liu J, Ericksen S S, Besspiata D, Fisher C W, Szklarz G D (2003) Characterization of substrate binding to cytochrome P450 1A1 using molecular modelling and kinetic analysis: case of residue 382. Drug Metabolism and Disposition 31:412-420.
9. Ching M S, Blake C L, Malek N A, Angus P W, Ghabrial H (2001) Differential inhibition of human CYP1A1 and CYP1A2 by quinidine and quinine. Xenobiotica 31:757-767.
10. Potter G A, Patterson L H, Wanogho E, Perry P J, Butler P C, Ijaz T, Ruparelia K C, Lamb J H, Farmer P B, Stanley L A, Burke M D (2002) The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1. British Journal of Cancer 86:774-778.
11. Zhang Z, Fasco M J, Huang Z, Guengerich F P, Kaminsky L S (1995) Human cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. Drug Metabolism and Disposition 23:1339-1345.
12. Gallagher E P, Kunze K L, Stapleton P L, Eaton D L (1996) The kinetics of aflatoxin B1 oxidation by human cDNA-expressed and human liver microsomal cytochromes P4501A2 and 3A4. Toxicology and Applied Pharmacology 141:595-606.
13. Hammons G J, Milton D, Stepps K, Guengerich F P, Tukey R H, Kadlubar F F (1997) Metabolism of carcinogenic heterocyclic and aromatic amines by recombinant human cytochrome P450 enzymes. Carcinogenesis 18:851-854.
14. Tassaneeyakul W, Mohamed Z, Birkett D J, McManus M E, Veronese M E, Tukey R H,Quattrochi L C, Gonzalez F J, Miners J O (1992) Caffeine as a probe for human cytochromes P450: validation using cDNA expression, immunoinhibition and microsomal kinetic and inhibitor techniques. Pharmacogenetics 2:173-183.
15. Tassaneeyakul W, Birkett D J, Edwards J W, Veronese M E, Tassaneeyakul W, Tukey R H, Miners J O (1996) Human cytochrome P450 isoform specificity in the regioselective metabolism of toluene and o-, m- and p-xylene. Journal of Pharmacology and Experimental Therapeutics 273:101-108.
16. Yamazaki H, Shaw P M, Guengerich F P, Shimada T (1998) Roles of cytochrome P450 1A2 and 3A4 in the oxidation of estradiol and estrone in human liver microsomes. Chemical Research in Toxicology 11:659-665.
17. Parikh A, Josephy P D, Guengerich F P (1999) Selection and characterization of human cytochrome P4501A2 mutants with altered catalytic properties. Biochemistry 38:5283-5289.
18. Guengerich F P (1999) Inhibition of oral contraceptive steroid-metabolizing enzymes by steroids and drugs. American Journal of Obstetrics and Gynecology 163:2159-2163.
19. FaccioláG, Midestrand M, von Baher C, Tybring G (2001) Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. European Journal of Clinical Pharmacology 56:881-888.
20. Ayivor S W, Baird J, Pritchard M P (2002) Recombinant human CYP1A2 catalyzes the O-demethylation of 7-methoxycoumarin. Drug Metabolism Reviews 34:Supplement 1, 46.
21. Turesky R J, Constable A, Richoz J, Varga N, Markovic J, Martin M V, Guengerich F P (1998) Activation of heterocyclic aromatic amines by rat and human liver microsomes and by purified rat and human cytochrome P4501A2. Chemical Research in Toxicology 11:925-936.
22. Rodrigues A D (1999) Integrated cytochrome P450 reaction phenotyping: attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes. Biochemical Pharmacology 57:465-480.
23. Zhao K, Murray S, Davies D S, Boobis A R, Gooderham N J (1994) Metabolism of the food derived mutagen and carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine (PhIP) by human liver microsomes. Carcinogenesis 15:1285-1288.
24. Becquemont L, Le Bot M A, Riche C, Funck-Brentano C, Jaillon P, Beaune P (1998) Use of heterologously expressed human cytochrome P4501A2 to predict tacrine-fluvoxamine drug interaction in man. Pharmacogenetics 8:101-108.
25. Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A, Raunio H (1998) Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica 28:1203-1253.
26. Le Gal A, Dreano Y, Lucas D, Berthou F (2003) Diversity of selective environmental substrates for human cytochrome P450 2A6: alkoxyethers, nicotine, coumarin, N-nitrosodiethylamine and N-nitrosobenzylmethylamine. Toxicology Letters 144:77-91.
27. Nakajima, M., Tamamoto, T., Nunoya, K.-I., Yokoi, T., Nagashima, K., Inoue, K., Funae, Y., Shimada N, Kamataki T, Kuroiwa Y (1996) Characterization of CYP2A6 involved in 3'-hydroxylation of cotinine in human liver microsomes. Journal of Pharmacology and Experimental Therapeutics 277:1010-1015.
28. Walter B A, Hundal J S (1994) In vitro metabolism of fadrozole (CGS16949A) in human microsomes and human cell lines expressing a single P450 isozyme. 6th North American ISSX Meeting, Volume 6, Raleigh, North Carolina, p.187.
29. Gillam E M J, Notley L M, Cai H, De Voss J J, Guengerich F P (2000) Oxidation of indole bycytochrome P450 enzymes. Biochemistry 39:13817-13824.
30. Messina E S, Tyndale R F, Sellers E M (1997) A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes, Journal of Pharmacology and Experimental Therapeutics 282:1608-1614.
31. Jones B C, Tyman C A, Smith D A (1997) Identification of the cytochrome P450 isoforms involved in O-demethylation of 4-nitroanisole in human liver microsomes. Xenobiotica 27:1025-1037.
32. Su T, Bao Z, Zhang Q-Y, Smith T J, Hong J-Y, Ding X (2000) Human cytochrome P450 CYP2A13: predominant expression in the respiratory tract and its high efficiency metabolic activation of a tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Cancer Research 60:5074-5079.
33. Reigh G, McMahon H, Ishizaki M, Ohara T, Shimane K, Esumi Y, Green C, Tyson C, Ninomiya S-I (1996) Cytochrome P450 species involved in the metabolism of quinoline. Carcinogenesis 17:1989-1996.
34. Nunoya K-I, Yokoi Y, Kimura K, Kodama T, Funayama M, Inoue K, Nagashima K, Funae Y, Shimada N, Green C, Kamataki T (1996) (+)-Cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride (SM-12502) as a novel substrate for cytochrome P4502A6 in human liver microsomes. Journal of Pharmacology and Experimental Therapeutics 277:768-774.
35. Komatsu T, Yamazaki H, Shimada N, Nakajima H, Yokoi T (2000) Roles of cytochromes P450 1A2, 2A6 and 2C8 in 5-fluorouracial formation from tegafur, an anticancer prodrug, in human liver microsomes. Drug Metabolism and Disposition 28:1457-1463.
36. Ekins S, Bravi G, Ring B J, Gillespie T A, Gillespie J S, VandenBranden M, Wrighton S A, Wikel J H (1999) Three-dimensional quantitative structure activity relationship analyses of substrates for CYP2B6. Journal of Pharmacology and Experimental Therapeutics 288:21-29.
37. Ekins S, Wrighton S A (1999) The role of CYP2B6 in human xenobiotic metabolism. Drug Metabolism Reviews 31:719-754.
38. Ekins S, Ring B J, Hall S D, Wrighton S A (1998) Autoactivation and activation of the cytochrome P450s. International Journal of Clinical Pharmacology and Therapeutics 36:642-651.
39. Pearce R E, Vakkalagadda G R, Leeder J S (2002) Pathways of carbamazepine bioactivation in vitro 1. Characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites. Drug Metabolism and Disposition 30:1170-1179.
40. Huang Z, Roy P, Waxman D J (2000) Role of human liver microsomal CYP3A4 and CYP2B6 in catalyzing N-dechloroethylation of cyclophosphamide and ifosfamide. Biochemical Pharmacology 59:961-972.
41. Hidestrand M, Oscarson M, Salonen J S, Nyman L, Pelkonen O, Turpeinen M, Ingelman-Sundberg M (2001) CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson's Disease, as revealed from experiments with recombinant enzymes. Drug Metabolism and Disposition 29:1480-1484.
42. Wang Q, Halpert J R (2002) Combined three-dimensional quantitative structure-activity relationship analysis of cytochrome P450 2B6 substrates and protein homology modeling. Drug Metabolism and Disposition 30:86-95.
43. Ohyama K, Nakajima M, Nakamura S, Shimada N, Yamazaki H, Yokoi T (2000) Asignificant role of human cytochrome P450 CYP2C8 in amiodarone N-deethylation: an approach to predict the contribution with relative activity factor. Drug Metabolism and Disposition 28:1303-1310.
44. Li X-Q, Bjorkman A, Andersson T B, Ridderstrom M, Masimirembwa C M (2002) Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. Journal of Pharmacology and Experimental Therapeutics 300:399-407.
45. Zeldin D C, Moomaw C R, Jesse N, Tomer K B, Beetham J, Hammock B D, Wu S (1996) Biochemical characterization of the human liver cytochrome P450 arachidonic acid epoxygenase pathway. Archives of Biochemistry and Biophysics 330:87-96.
46. Miller V P, Stresser D M, Blanchard A P, Turner S, Crespi C L (2000) Fluorometric high-throughput screening for inhibitors of cytochrome P450. Annals of the New York Academy of Sciences 919:26-32.
47. Mancy A, Antignac M, Minoletti C, Dijols S, Mouries V, Ha Duong N-T, Battioni P, Dansette P M, Mansuy D (1999) Diclofenac and its derivatives as tools for studying human cytochromes P450 active sites: particular efficiency and regioselectivity of P4502Cs. Biochemistry 38:14264-14270.
48. Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck J-P, Robinson W T (1999) The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochorme P450 and implications for metabolic drug interactions. Drug Metabolism and Disposition 27:410-416.
49. Nadin L, Murray M (1999) Participation of CYP2C8 in retinoic acid 4-hydroxylation in human hepatic microsomes. Biochemical Pharmacology 58:1201-1208.
50. Leo M A, Lasker J M, Raucy J L, Kim C-I, Black M, Lieber C S (1989) Metabolism of retinol and retinoic acid by human liver cytochrome P450IIC8. Archives of Biochemistry and Biophysics 269:305-312.
51. Baldwin S J, Clarke S E, Chenery R J (1999) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. British Journal of Clinical Pharmacology 48:424-432.
52. Crespi C L, Chang T K H, Waxman D J (1998) High-performance liquid chromatographic analysis of CYP2C8-catalyzed paclitaxel 6α-hydroxylation, in: Cytochrome P450 Protocols (I.R. Phillips and E.A. Shephard, eds.) Humana Press, Totowa, New Jersey, 123-127.
53. Sahi J, Black C B, Hamilton G A, Zheng X, Jolley S, Rose K A, Gilbert D, Le Cluyse E L, Sinz M W (2003) Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metabolism and Disposition 31:439-446.
54. Bonnabry P, Leeman T, Dayer P (1994) Biotransformation by hepatic P450TB (CYP2C) controls mefenamic acid elimination. Clinical Pharmacology and Therapeutics 55:139.
55. Bonnabry P, Leeman T, Dayer P (1996) Role of human liver microsomal CYP2C9 in the biotransformation of lornoxicam. European Journal of Clinical Pharmacology 49:305-308.
56. Stearns R A, Chakravarty P K, Chen R, Lee Chiu S-H (1995) Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Drug Metabolism and Disposition 23:207-215.
57. Bajpai M, Roskos L K, Shen D D, Levy R H (1996) Roles of cytochrome P4502C9 and cytochrome P4502C19 in the stereoselective metabolism of phenytoin to its major metabolite.Drug Metabolism and Disposition 24:1401-1403.
58. Leeman T D, Transon C, Bonnabry P, Dayer P (1993) A major role for cytochrome P450TB (CYP2C subfamily) in the actions of non-steroidal anti-inflammatory drugs. Drugs Under Experimental Clinical Research 19:189-195.
59. Takanashi K, Tainaka H, Kobayashi K, Yasumori T, Hosakawa M, Chiba K (2000) CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates. Pharmacogenetics 10:95-104.
60. Yamazaki H, Suzuki M, Tane K, Shimada N, Nakajima M, Yokoi T (2000) In Vitro inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human cytochrome P450 enzymes: comparison with pioglitazone and rosiglitazone. Xenobiotica 30:61-70.
61. McGinnity D F, Griffin S J, Moody G C, Voice M, Hanlon S, Freidberg T, Riley R J (1999) Rapid characterization of the major drug-metabolizing human hepatic cytochrome P450 enzymes expressed in Escherichia coli. Drug Metabolism and Disposition 27:1017-1023.
62. Knodell R G, Dubey R K, Wilkinson G R, Guengerich F P (1988) Oxidative metaboism of hexobarbital in human liver: relationship to polymorphic S-mephenytoin 4-hydroxylation, Journal of Pharmacology and Experimental Therapeutics 245:845-849.
63. Miyazawa M, Shindo M, Shimada T (2002) Metabolism of (+)- and (-)-limonenes to respective carveols and perillyl alcohols by CYP2C9 and CYP2C19 in human liver microsomes. Drug Metabolism and Dispostion 30:603-607.
64. FaccioláG, Midestrand M, von Baher C, Tybring G. (2001) Cytochrome P450 isoforms involved in melatonin metabolism in human liver microsomes. European Journal of Clinical Pharmacology 56:881-888.
65. Tsao C-C, Wester M R, Ghanayem B, Coulter S J, Chanas B, Johnson E F, Goldstein J A (2001) Identification of human CYP2C19 residues that confer S-mephenytoin 4'-hydroxylase activity to CYP2C9. Biochemistry 40:1937-1944.
66. Kobayashi K, Kogo M, Tani M, Shimada N, Ishizaki T, Numazawa S, Yoshida T, Yamamoto T, Kuroiwa Y, Chiba K (2001) Role of CYP"C19 in stereoselective hydroxylation of mephobarbital by human liver microsomes. Drug Metabolism and Disposition 29:36-40.
67. Hoskins J, Shenfield G., Murray M, Gross A (2001) Characterization of moclobemide N-oxidation in human liver microsomes. Xenobiotica 31:387-397.
68. Andersson T, Miners J O, Veronese M E, Tassaneeyakul W, Tassaneeyakul W, Meyer U A, Birkett D J (1993) Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. British Journal of Clinical Pharmacology 36:521-530.
69. Birkett D J, Rees D, Andersson T, Gonzalez F J, Miners J O, Veronese M E (1994) In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylase. British Journal of Clinical Pharmacology 37:413-420.
70. VandenBranden M, Ring B J, Binkley S N, Wrighton S A (1996) Interaction of human liver cytochromes P450 in vitro with LY307640, a gastric proton pump inhibitor. Pharmacogenetics 6:81-91.
71. Wienkers L C, Wurden C J, Storch E, Kunze K L, Rettie A E, Trager W F (1996) Formation of (R)-8-hydroxywarfarin in human liver microsomes: a new metabolic marker for the (S)-mephenytoin hydroxylase P4502C19. Drug Metabolism and Disposition 24:610-614.
72. Kedderis G L, Batra R, Koop D R (1993) Epoxidation of acrylonitrile by rat and humancytochromes P450. Chemical Research in Toxicology 6:866-871.
73. BourriéM, Meunier V, Berger Y, Fabre G (1996) Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions catalyzed by human liver microsomes. Journal of Pharmacology and Experimental Therapeutics 277:321-332.
74. Nedelcheva V, Gut I, Soucek P, Tichavska B, Tynkova L, Mraz J, Guengerich F P, Ingelman-Sundberg M (1999) Metabolism of benzene in human liver microsomes: individual variations in relation to CYP2E1 expression. Archives of Toxicology 73:33-40.
75. Zhao G, Allis J W (2002) Kinetics of bromodichloromethane metabolism by cytochrome P450 isoenzymes in human liver microsomes. Chemico-Biological Interactions 140: 155-168.
76. Duescher R J, Elfarra A A (1994) Human liver microsomes are efficient catalysts of 1,3-butadiene oxidation: evidence for major roles by cytochromes P4502A6 and 2E1. Archives of Biochemistry and Biophysics 311:342-349.
77. Mitra A, Thummel K E, Kalhorn T F, Kharasch E D, Unadkat J D, Slattery J T (1995) Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo. Clinical Pharmacology and Therapeutics 58:556-566.
78. Bell L C, Guengerich F P (1997) Oxidation kinetics of ethanol by human cytochrome P450
2E1. Journal of Biological Chemistry 272:29643-29651.
79. Bachmann K, He Y, Sarver J G, Peng N (2003) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of ethosuximide by human hepatic microsomal enzymes. Xenobiotica 33:265-276.
80. Spracklin D K, Hankins D C, Fisher J M, Thummel K E, Kharasch E D (1997) Cytochrome P450 2E1 is the principal catalyst of human oxidative halothane metabolism in vitro. Journal of Pharmacology and Experimental Therapeutics 281:400-411.
81. Bogaards J J P, Freidig A P, van Bladeren P J (2001) Prediction of isoprene diepoxide levels in vivo in mouse, rat and man using enzyme kinetic data in vitro and physiologically-based pharmacokinetic modelling. Chemico-Biological Interactions 138:247-265.
82. Clarke S E, Baldwin S J, Bloomer J C, Ayrton A D, Sozio R S, Chenery R J (1994) Lauric acid as a model substrate for the simultaneous determination of cytochrome P4502E1 and 4A in hepatic microsomes. Chemical Research in Toxicology 7:836-842.
83. Chen W, Koenigs L L, Thompson S J, Peter R M, Rettie A E, Trager W F, Nelson S D (1998) Oxidation of acetamidophen to its toxic quinone imine and nontoxic catechol by baculovirus-expressed and purified human cytochromes P4502E1 and 2A6. Chemical Research in Toxicology 11:295-301.
84. Carlson G P, Mantick N A, Powley M W (2000) Metabolism of styrene by human liver and lung. Journal of Toxicology and Environmental Health 59:591-595.
85. Dupont I, Berthou F, Bodenez P, Bardou L, Guirriec C, Stephan N, Dreano Y, Lucas D (1999) Involvement of cytochromes P450 2E1 and 3A4 in the 5-hydroxylation of salicylate in humans. Drug Metabolism and Disposition 27:322-326.
86.徐筱杰,等.计算机辅助药物分子设计.化学工业出版社,北京:2004.
87. Vapnik V (2000) The nature of statistical learning theory. Springer Verlag.
88. Toutios A, Margaritis K (2005) Mapping between the speech signal and articulatory trajectories. Proceedings of the 7th HERCMA
1. Bradshaw R A, Brickey W W, Walker K W (1998) N-Terminal processing: the methionine aminopeptidase and Nα-acetyl transferase families. Trends Biochem Sci 23:263–267.
2. Lowther W T, Matthews B W (2000) Structure and function of the methionine aminopeptidase. Biochim Biophys Acta 1477:157–167.
3. Wang J, Sheppard G S, Lou P, Kawai M, BaMaung N, Erickson S A, Tucker-Garcia L, Park C, Bouska J, Wang Y C, et al. (2003) Tumor Suppression by a Rationally Designed Reversible Inhibitor of Methionine Aminopeptidase-2 Cancer Res 63:7861–7869.
4. Bernier S G, Lazarus D D, Clark E, Doyle B, Labenski M T, Thompson C D, Westlin W F, Hannig G (2004) A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis. Proc Natl Acad Sci USA 101:10768–10773.
5. Vaughan M D, Sampson P B, Honek J F (2002) Methionine in and out of protein: targets for drug design. Curr Med Chem 9:385–409.
6. Zhang P, Nicholson D E, Bujnicki J M, Su X, Brendle J J, Ferdig M, Kyle D E, Milhous W K, Chiang P K (2002) Angiogenesis inhibitors specific for methionine aminopeptidase 2 as drugs for Malaria and Leishmaniasis. J Biomed Sci 9:34–40.
7. Cramer III R D Paterson D E, Bunce J D (1988) Comparative molecular-field analysis (CoMFA) .1. effect of shape on binding of steroids to carrier proteins. J Am Chem Soc
110:5959-5967.
8. Clark M, Cramer III R D (1993) The Probability of Chance Correlation Using Partial Least Squares (PLS). Quant Struct-Act Relat 12:137-145.
9. Klebe G, Abraham U, Mietzner T (1994) Molecular Similarity Indices in a Comparative Analysis (CoMSIA) of Drug Molecules to Correlate and Predict their Biological Activity. J Med Chem 37:4130-4146.
10. B?hm M, Stürzebecher J, Klebe G (1999) 3D QSAR Analyses using CoMFA and CoMSIA to Elucidate Selectivity Differences of Inhibitors Binding to Trypsin, Thrombin and Factor Xa. J Med Chem 42:458-477.
11. Stanton D T, Jurs P C (1990) Development and use of charged partial surface area descriptors in computer-assisted quantitative structure-property relationship studies. Anal Chem 62:2323-2329.
12. Clementi S, Cruciani G, Fifi P, Riganelli D, Valigi R, Musumarra G (1995) A new set of principal properties for heteroaromatics obtained by GRID. Quant Struct-Act Relat
15:108-120.
13. Goodford P J (1995) A computational procedure for determining energetically favourable binding sites on biologically important macromolecules. J Med Chem 28(7):849-857.
14. Pommier Y, Jaxel C, Heise C R, et al. SAR of topoisomeraseⅠinhibition by camptothecin derivatives: evidence for the existence of a ternary complex. In: Potmesil M, Kohn KW, ed. DNA topoisomerase in cancer. Oxford Univ Press, New York: 1991:121-132.
15. Vapnik V (2000) The nature of statistical learning theory. Springer Verlag.
16. Toutios A, Margaritis K (2005) Mapping between the speech signal and articulatory trajectories. Proceedings of the 7th HERCMA.
17. Schwede T, Kopp J, Guex N, Peitsch M C (2003) SWISS-MODEL: an automated proteinhomology-modelling server. Nucleic Acids Res, 31:3381-3385.
18. Stahle L, Wold S, Ellis G P, West G B (1988) Progress in Medicinal Chemistry. Elsevier, Amsterdam, The Netherlands 1988, 292–338.
19. Klebe G, Abraham U (1999) Comparative Molecular Similarity Index Analysis (CoMSIA) to Study Hydrogen Bonding Properties and to Score CombinatorialLibraries. J Comput Aided Mol Des 13:1-10.
20. Hall L H, Kier L B (1991) The Molecular Connectivity Chi Indices and Kappa Shape Indices in Structure-Property Modeling. Reviews of Computational Chemistry. 2.
21. Chang C, Lin C (2001) LIBSVM: a library for support vector machines.