Computational Modeling of Receptor-Mediated Toxicity

Computational Toxicology: Risk Assessment for Pharmaceutical and Environmental Chemicals

Volumn , Issue , 2006, Pages 315-351

  Lill, Markus A ^a,b   Vedani, Angelo ^a,b  

^a UNIVERSITY OF BASEL   (Switzerland)

^b Biographics Laboratory 3R   (Switzerland)

Author keywords

Adverse drug drug interactions and CYP induction; Computational modeling of receptor mediated toxicity; Receptors involved in toxicity

Indexed keywords

EID: 67349249455     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9780470145890.ch12     Document Type: Chapter

References (197)

1. Tsai MJ, Omalley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. An Rev Biochem 1994;63:451-86.
2. Ribeiro RCJ, Kushner PJ, Baxter JD. The nuclear hormone-receptor gene superfamily. An Rev Med 1995;46:443-53.
3. Moras D, Gronemeyer H. The nuclear receptor ligand-binding domain: Structure and function. Curr Opin Cell Biol 1998;10:384-91.
4. Katzenellenbogen JA, Katzenellenbogen BS. Nuclear hormone receptors: Ligand-activated regulators of transcription and diverse cell responses. Chem Biol 1996;3:529-36.
5. Gray LE, Kelce WR, Wiese T, Tyl R, Gaido K, Cook J, et al. Endocrine screening methods workshop report: Detection of estrogenic and androgenic hormonal and antihormonal activity for chemicals that act via receptor or steroidogenic enzyme mechanisms. Reprod Toxicol 1997;11:719-50.
6. Weatherman RV, Fletterick RJ, Scanlan TS. Nuclear-receptor ligands and ligand-binding domains. An Rev Biochem 1999;68:559-81.
7. Damstra T, Barlow S, Bergman A, Kavlock R, van der Kraak G, editors. Global assessment of the state of the science of endocrine disruptors. Geneva: World Health Organization, 2002, ch. 5.4, and references therein.
8. Damstra T, Barlow S, Bergman A, Kavlock R, van der Kraak G, editors. Global assessment of the state of the science of endocrine disruptors. Geneva: World Health Organization, 2002, ch. 5.1, and references therein.
9. Damstra T, Barlow S, Bergman A, Kavlock R, van der Kraak G, editors. Global assessment of the state of the science of endocrine disruptors. Geneva: World Health Organization, 2002, chs. 3.14 and 5.2, and references therein.
10. Carson R. Silent spring. Boston: Houghton Mifflin, 2002.
11. Schurmeyer T, Nieschlag E. Effect of ketoconazole and other imidazole fungicides on testosterone biosynthesis. Acta Endocrinol 1984;105:275-80.
12. Pepper G, Brenner S, Gabrilove J. Ketoconazole use in the treatment of ovarian hyperandrogenism. Fertil Steril 1990;54:38-44.
13. Williams DR, Fisher MJ, Rees HH. Characterization of ecdysteroid 26-hydroxylase: An enzyme involved in molting hormone inactivation. Arch Biochem Biophys 2000;376:389-98.
14. Sheehan DM, Young M. Diethylstilbestrol and estradiol binding to serum-albumin and pregnancy plasma of rat and human. Endocrinology 1979;104:1442-46.
15. Birnbaum LS. Endocrine effects of prenatal exposure to PCBs, dioxins and other xenobiotics: Implications for policy and research. Environ Health Perspect 1994;102:676-9.
16. Kuiper GGJM, Gustafsson J-A. The novel estrogen receptor-β subtype: Potential role in the cell-and promoterspecific actions of estrogens and anti-estrogens. FEBS Lett 1997;410:87-90.
17. Kuiper GGJM, Carlsson B, Grandien K, Enmark E, Haeggblad J, et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology 1997;138:863-70.
18. Hewitt SC, Couse JF, Korach KS. Estrogen receptor transcription and transactivation. Estrogen receptor knockout mice: What their phenotypes reveal about mechanisms of estrogen action. Breast Cancer Res 2000;2:345-52.
19. Couse JF, Korach KS. Estrogen receptor null mice: What have we learned and where will they lead us? Endocr Rev 1999;20:358-417.
20. α) and β (ERβ) on mouse reproductive phenotypes. Development 2000;127:4277-91.
21. Barkhem T, Carlsson B, Nilsson Y, Enmark E, Gustafsson J, Nilsson S. Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol Pharmacol 1998;54:105-12.
22. Dibb S. Swimming in a sea of estrogens, chemical hormone disrupters. Ecologist 1995;25:27-31.
23. McLachlan JA, Arnold SF. Environmental estrogens. Am Sci 1996;84:452-61.
24. Guillette LJ, Crain DA, Rooney AA, Pickford DB. Organization versus activation: The role of endocrine disrupting contaminants EDCs during embryonic development in wildlife. Environ Health Perspect 1995;103:157-64.
25. Colborn T. Environmental estrogens: Health implications for humans and wildlife. Environ Health Perspect 1995;103:135-36.
26. Feldman D, Krishnan A. Estrogens in unexpected places: Possible implications for researchers and consumers. Environ Health Perspect 1995;103:129-33.
27. Hoare SA, Jobling S, Parker MG, Sumpter JP, White R. Environmental persistent alkylphenolic compounds are estrogenic. Endocrinology 1994;135:175-82.
28. Korach KS, Levy LA, Sarver PJ. Estrogen receptor stereochemistry: Receptor binding and hormonal responses. J Steroid Biochem 1987;27:281-90.
29. Safe Drinking Water Act Amendment; Public Law 104-182 (Section 136); US Environmental Protection Agency, 1996 .
30. Food Quality Protection Act; Public Law 104-170 (Section 408); US Food and Drug Administration, 1996 .
31. Fang H, Tong W, Welsh WJ, Sheehan, DM. QSAR models in receptor-mediated effects: the nuclear receptor superfamily. J Molec Structure 2003;622:113-25.
32. Schmieder PK, Ankley G, Mekenyan O, Walker JD. Quantitative structure-activity relationship models for prediction of estrogen receptor binding affinity of structurally diverse chemicals. Environ Toxicol Chem 2003;22:1844-54.
33. 2! J Mol Graphics Model 2002;20:269-76.
34. BioByte Corp.201 W. 4th St., #204 Claremont, CA 91711-4707.
35. Gao H, Katzenellenbogen JA, Garg R, Hansch C. Comparative QSAR Analysis of estrogen receptor ligands. Chem Rev 1999;99:723-44.
36. Gao H, Williams C, Labute P, Bajorath J. Binary quantitative structure-activity relationship (QSAR) analysis of estrogen receptor ligands. J Chem Inf Comput Sci 1999;39:164-8.
37. Zheng W, Tropsha A. Novel variable selection quantitative structure-property relationship approach based on the A>nearest-neighbor principle. J Chem Inf Comput Sci 2000;40:185-94.
38. Kier LB, Hall LH. Molecular connectivity in chemistry and drug research. New York: Academic Press, 1976.
39. Kier LB, Hall LH. Molecular connectivity in structure-activity analysis. Chichester: Research Studies Press, 1986.
40. Hall LH, Kier LB. The molecular connectivity chi indexes and kappa shape indexes in structure-property modeling. In: Lipkowitz KB, Boyd DB, editors, Reviews in computational chemistry II. Weinheim: VCH, 1991;367-422.
41. Carhart RE, Smith DH, Venkataraghavan R. Atom pairs as molecular features in structure-activity studies: Definition and applications. J Chem Inf Comput Sci 1985;25:64-73.
42. Asikainen A, Ruuskanen J, Tuppurainen K. Consensus kNN QSAR: A versatile method for predicting the estrogenic activity of organic compounds in silico: A comparative study with five estrogen receptors and a large, diverse set of ligands. Environ Sci Technol 2004;38:6724-9.
43. .
44. Todeschini R, Consonni V, Pavan M. DRAGON. Software for the calculation of molecular descriptors, Version 3.0.
45. Marini F, Roncaglioni A, Novic M. Variable selection and interpretation in struc-ture-affinity correlation modeling of estrogen receptor binders. J Chem Inf Model 2005;45:1507-19.
46. Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL, et al. The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci 2000;54:138-53.
47. Brown N, McKay B, Gasteiger J. Fingal: A novel approach to geometric fingerprinting and a comparative study of its application to 3D-QSAR modelling. QSAR Comb Sci 2005;24:480-4.
48. Mekenyan O, Ivanov J, Karabunarliev S, Bradbury S, Ankley G, Karcher W. A computationally-based hazard identification algorithm that incorporates ligand flexibility: 1. Identification of potential androgen receptor ligands. Environ Sci Technol 1997;31:3702-11.
49. Mekenyan O, Nikolova N, Karabunarliev S, Bradbury S, Ankley G, Hansen, B. New developments in a hazard identification algorithm for hormone receptor ligands. Quant Struct-Act Rel 1999;18:139-53.
50. Mekenyan O, Kamenska V, Serafimova R, Poellinger L, Brouwer A, Walker J. Development and validation of an average mammalian estrogen receptor-based QSAR model. SAR QSAR Environ Res 2002;13:579-95.
51. Cramer R III, Patterson DE, Bunce JD. Comparative molecular field analysis (CoMFA): 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 1988;110:5959-67.
52. Waller CL, Oprea TI, Chae K, Park H-E, Korach KS, Laws SC, et al. ligand-based identification of environmental estrogens. Chem Res Toxicol 1996;9:1240-8.
53. Kellogg GE, Semus SF, Abraham DJ. HINT: A new method of empirical hydrophobic field calculation for CoMFA. J Comput Aided Mol Des 1991;5:545-52.
54. Demyttenaere-Kovatcheva A, Cronin MTD, Benfenati E, Roncaglioni A, LoPiparo E. Identification of the structural requirements of the receptor-binding affinity of diphenolic azoles to estrogen receptors α and β by three-dimensional quantitative structure-activity relationship and structure-activity relationship analysis. J Med Chem 2005;48:7628-36.
55. Coleman KP, Toscano WA Jr, Wiese TE. QSAR models of the in vitro estrogen activity of bisphenol A analogs. QSAR Comb Sci 2003;22:78-88.
56. Shi LM, Fang H, Tong W, Wu J, Perkins R, Blair RM, et al. QSAR models using a large diverse set of estrogens. J Chem Inf Comput Sci 2001;41:186-95.
57. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology 1998;139:4252-63.
58. Wiese TE, Polin LA, Palomino E, Brooks SC. Induction of the estrogen specific mitogenic response of MCF-7 cells by selected analogues of estradiol-17 beta: A 3D QSAR study. J Med Chem 1997;40:3659-69.
59. Tong W, Perkins R, Xing L, Welsh WJ, Sheehan DM. QSAR models for binding of estrogenic compounds to estrogen receptor alpha and beta subtypes. Endocrinology 1997;138:4022-5.
60. 2-guided region selection approach. J Med Chem 1998;41:2261-7.
61. Gantchev TG, Ali H, van Lier JE. Quantitative structure-activity relationships/ comparative molecular field analysis (QSAR/CoMFA) for receptor-binding properties of halogenated estradiol derivatives. J Med Chem 1994;37:4164-76.
62. .
63. Fang H, Tong W, Shi LM, Blair R, Perkins R, Branham W, et al. Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens. Chem Res Toxicol 2001;14:280-94.
64. Shi LM, Tong W, Fang H, Perkins R, Wu J, Tu M, et al. An integrated "4-phase" approach for setting endocrine disruption screening priorities-Phase I and II predictions of estrogen receptor binding affinity. SAR QSAR Environ Res 2002;13:69-88.
65. Hong H, Tong W, Fang H, Shi LM, Xie Q, Wu J, et al. Prediction of estrogen receptor binding for 58,000 chemicals using an integrated system of a tree-based model with structural alerts. Environ Health Perspect 2002;110:29-36.
66. .
67. Tong W, Hong H, Fang H, Xie Q, Perkins R. Decision forest: Combining the predictions of multiple independent decision tree models. J Chem Inf Comput Sci 2003;43:525-31.
68. Tong W, Xie Q, Hong H, Shi LM, Fang H, Perkins R. Assessment of prediction confidence and domain extrapolation of two structure-activity relationship models for predicting estrogen receptor binding activity. Environ Health Perspect 2004;112:1249-54.
69. Jacobsson M, Lidén P, Stjernschantz E, Boström H, Norinder U. Improving structure-based virtual screening by multivariate analysis of scoring data. J Med Chem 2003;46:5781-9.
70. Abagyan R, Totrov M. ICM online manual .
71. Abagyan R, Totrov M. Biased probability Monte Carlo conformational searches and electrostatic calculations for peptides and proteins. J Mol Biol 1994;235:983-1002.
72. Clark RD, Strizhev A, Leonard JM, Blake JF, Matthew JB. Consensus scoring for ligand-protein interactions. J Mol Graphics Model 2002;20:281-95.
73. Rarey M, Kramer B, Lengauer T, Klebe G. A fast flexible docking method using an incremental construction algorithm. J Mol Biol 1996;261:470-89.
74. Kuntz ID, Blaney JM, Oatley SJ, Langridge R, Ferrin TE. A geometric approach to macromolecule-ligand interactions. J Mol Biol 1982;161:269-88.
75. Muegge I, Martin YC. A general and fast scoring function for protein-ligand interactions: A simplified potential approach. J Med Chem 1999;42:791-804.
76. Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Biol 1997;267:727-48.
77. Eldridge MD, Murray CW, Auton TR, Paolini GV, Mee RP. Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J Comput Aided Mol Des 1997;11:425-45.
78. Wold S, Johansson E, Cocchi M. PLS-partial least-squares projections to latent structures. In 3D QSAR in Drug Design. Leiden: ESCOM, 1993. p. 523-50.
79. Rule Discovery System (RDS) 0.8 ; Compumine AB.
80. Domingos P, Pazzani M. On the optimality of the simple Bayesian classifier under zero-one loss. Mach Learn 1997;29:103-30.
81. Prathipati P, Saxena AK. Evaluation of binary qsar models derived from ludi and moe scoring functions for structure based virtual screening. J Chem Inf Model 2006;46:39-51.
82. Labute P. Binary QSAR: A new method for the determination of quantitative structure-activity relationships. In Altman RB, Dunker AK, Hunter L, Klein TE, Lauderdale K, editors, Proceedings of the Pacific Symposium on Biocomputing '99. River Edge, NJ: World Scientific, p. 444-55.
83. Bohm HJ. The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure. J Comput Aided Mol Des 1994;8:243-56.
84. Bohm HJ. Prediction of binding constants of protein ligands: a fast method for the prioritization of hits obtained from de novo design or 3D database search programs. J Comput Aided Mol Des 1998;12:309-23.
85. Chemical Computing Group, MOE, Quebec, Canada, 2004.
86. Akahori Y, Nakai M, Yakabe Y, Takatsuki M, Mizutani M, Matsuo M, et al. Two-step models to predict binding affinity of chemicals to the human estrogen receptor a by three-dimensional quantitative structure-activity relationships (3D-QSARs) using receptor-ligand docking simulation. SAR QSAR Environ Res 2005;16:323-37.
87. Institute of Medicinal Molecular Design Inc. Japan .
88. Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KM Jr, Ferguson DM, et al. A second generation force field for the simulation of proteins, nucleic acids and organic molecules. J Am Chem Soc 1995;117:5179-97.
89. Sippl W. Binding affinity prediction of novel estrogen receptor ligands using receptor-based 3-D QSAR methods. Bioorg Med Chem 2002;10:3741-55.
90. Rao MS, Olson AJ. Modelling of factor Xa-inhibitor complexes: A computational flexible docking approach. Prot Struct Funct Gen 1999;34:173-83.
91. Vedani A, Huhta DW. A new force field for modeling metalloproteins. J Am Chem Soc 1990;112:4759-67.
92. Baroni M, Costantino G, Cruciani G, Riganelli D, Valigi R, Clementi S. Generating optimal linear PLS estimations (GOLPE): An advanced chemometric tool for handling 3D-QSAR problems. Quant Struct-Act Rel 1993;12:9-20.
93. Lemmen C, Lengauer T, Klebe G. FLEXS: A method for fast flexible ligand superposition. J Med Chem 1998;41:4502-20.
94. Vedani A, Dobler M, Lill MA. Combining protein modeling and 6D-QSAR. simulating the binding of structurally diverse ligands to the estrogen receptor. J Med Chem 2005;48:3700-3.
95. .
96. Vedani A, Briem H, Dobler M, Dollinger K, McMasters DR. Multiple conformation and protonation-state representation in 4D-QSAR: The neurokinin-1 receptor system. J Med Chem 2000;43:4416-27.
97. Vedani A, Dobler M. 5D-QSAR: The key for simulating induced fit? J Med Chem 2002;45:2139-49.
98. .
99. Lill MA, Vedani A, Dobler M. Raptor-Combining dual-shell representation, induced-fit simulation and hydrophobicity scoring in receptor modeling: Application towards the simulation of structurally diverse ligand sets. J Med Chem 2004;47:6174-86.
100. Lill MA, Dobler M, Vedani A. Prediction of small-molecule binding to cytochrome P450 3A4: Flexible docking combined with multidimensional QSAR. ChemMedChem. 2006;1:73-81.
101. .
102. U.S. Food and Drug Administration .
103. Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004.
104. Heinlein CA, Chang CS. Androgen receptor in prostate cancer. Endocr Rev 2004;25:276-308.
105. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol 1984;132:474-9.
106. Fang H, Tong W, Branham WS, Moland CL, Dial SL, Hong H, et al. Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor. Chem Res Toxicol 2003;16:1338-58.
107. Araki N, Ohno K, Nakai M, Takeyoshi M, Iida M. Screening for androgen receptor activities in 253 industrial chemicals by in vitro reporter gene assays using AR-EcoScreen cells. Toxicol In Vitro 2005;19:831-42.
108. Kojima H, Katsura E, Takeuchi S, Niiyama K, Kobayashi K. Screening for estrogen and androgen receptor activities in 200 pesticides by in vitro reporter gene assays using Chinese hamster ovary cells. Environ Health Perspect 2005;112:524-31.
109. Carlsen E, Giwercman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of semen during past 50 years. Br Med J 1992;305:609-13.
110. Kavlock RJ, Daston GP, DeRosa C, Fenner-Crisp P, Gray LE, Kaattari S. Research needs for the risk assessment of health and environmental effects of endocrine disruptors: A report of the U.S. EPA-sponsored workshop. Environ Health Perspect 1996;104:715-40.
111. Damstra T, Barlow S, Bergman A, Kavlock R, van der Kraak G, editors. Global assessment of the state of the science of endocrine disruptors. Geneva: World Health Organization, 2002, ch. 3.12.
112. Toft G, Edwards TM, Baatrup E, Guillette LJ Jr. Disturbed sexual characteristics in male mosquitofish (Gambusia holbrooki) from a lake contaminated with endocrine disruptors. Environ Health Perspect 2003;111:695-701.
113. Kelce WR, Wilson EM. Environmental antiandrogens: Developmental effects, molecular mechanisms, and clinical implications. J Mol Med 1997;75:198-207.
114. Jones I, Lindberg C, Jakobsson S, Hellqvist A, Hellman U, Borg B, et al. Molecular cloning and characterization of spiggin: An androgen-regulated extraorganis-mal adhesive with structural similarities to von willebrand factor-related proteins. J Biol Chem 2001;276:17857-63.
115. Katsiadaki I, Scott AP, Hurst MR, Matthiessen P, Mayer I. Detection of environmental androgens: A novel method based on enzyme-linked immunosorbent assay of spiggin, the stickleback (Gasterosteus aculeatus) glue protein. Environ Toxicol Chem 2002;21:1946-54.
116. Serafimova R, Walker J, Mekenyan O. Androgen receptor binding affinity of pesticide "active" formulation ingredients: QSAR evaluation by COREPA method. SAR QSAR Environ Res 2002;13:127-34.
117. Zhao CY, Zhang RS, Zhang HX, Xue CX, Liu HX, Liu MC, et al. QSAR study of natural, synthetic and environmental endocrine disrupting compounds for binding to the androgen receptor. SAR QSAR Environ Res 2005;16:349-67.
118. Waller CL, Juma BW, Gray LE Jr, Kelce WR Three-dimensional quantitative structure-activity relationships for androgen receptor ligands. Toxic Appl Pharm 1996;137:219-27.
119. Hong H, Fang H, Xie Q, Perkins R, Sheehan DM, Tong W. Comparative molecular field analysis (CoMFA) model using a large diverse set of natural, synthetic and environmental chemicals for binding to the androgen receptor. SAR QSAR Environ Res 2003;14:373-88.
120. Matias PM, Donner P, Coelho R, Thomaz M, Peixoto C, Macedo S, et al. Structural evidence for ligand specificity in the binding domain of the human androgen receptor: Implications for pathogenic gene mutations. J Biol Chem 2000;275:26164-71.
121. Söderholm AA, Lehtovuori PT, Nyrönen TH. Three-dimensional structure-activ-ity relationships of nonsteroidal ligands in complex with androgen receptor ligand-binding domain. J Med Chem 2005;48:917-25.
122. Sack JS, Kish KF, Wang C, Attar RM, Kiefer SE, et al. Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone. Proc Natl Acad Sci USA 2001;98:4904-9.
123. Bohl CE, Chang C, Mohler ML, Chen J, Miller DD, Swaan PW, et al. A ligand-based approach to identify quantitative structure-activity relationships for the androgen receptor. J Med Chem 2004;47:3765-76.
124. Lill MA, Winiger F, Vedani A, Ernst B. Impact of induced fit on ligand binding to the androgen receptor: A multidimensional QSAR study to predict endocrine-disrupting effects of environmental chemicals. J Med Chem 2005;48:5666-74.
125. Hansson T, Marelius J, Aqvist J. Ligand binding affinity prediction by linear interaction energy methods. J Comput Aided Mol Des 1998;12:27-35.
126. Lazar MA. Thyroid hormone receptors: Multiple forms, multiple possibilities. Endocrine Rev 1993;14:184-93.
127. Kavlock RJ, Daston GP, DeRosa C, Fenner-Crisp P, Gray LE, Kaattari S, et al. Research needs for the risk assessment of health and environmental effects of endocrine disruptors: A report of the U.S. EPA-sponsored workshop. Environ Health Perspect 1996;104:715-40.
128. Colborn T, von Saal FS, Soto AM. Developmental effects of endocrine-disrupting chemicals in wildlife and humans. Environ Health Perspect 1993;101:378-84.
129. Carlsen E, Giwercman A, Keiding N, Skakkebaek NE. Evidence for decreasing quality of semen during past fifty years. Br Med J 1992;305:609-13.
130. 1. J Med Chem 2003;46:1580-8.
131. Bruice TC, Kharash N, Winzler RJ. A correlation of thyroxine-like activity and chemical structure. Arch Biochem Biophys 1956;62:305-17.
132. Kubinyi H, Kehrhahn OH. Quantitative structure-activity relationships: 1. The modified free-Wilson approach. J Med Chem 1976;19:578-86.
133. Kubinyi H. Quantitative structure-activity relationships: 1. The modified free-Wilson approach. 2. A mixed approach, based on Hansch and Free-Wilson analysis. J Med Chem 1976;19:587-600.
134. Dietrich SW, Bolger MB, Kollman PA, Jorgensen EC. Thyroxine analogues: 23. Quantitative structure-correlation studies of in vivo and in vitro thyromimetic activities. J Med Chem 1977;20:863-80.
135. Leeson PD, Emmet JC, Shah VP, Showell GA, Novelli R, Prain HD, et al. Selective thyromimetics: Cardiac-sparing thyroid hormone analogs containing 3'-aryl-methyl substituents. J Med Chem 1989;32:320-36.
136. McKinney JD, Waller CL. Molecular determinants of hormone mimicry: Halo-genated aromatic hydrocarbon environmental agents. Toxicol Environ Health B Crit Rev 1998;1:27-58.
137. Zumstein M. Development of a quantitative structure-activity relationship for the α/β specificity of the human thyroid hormone receptor. M.Sc. thesis. University of Basel, Switzerland, 2005.
138. Vedani A, Zumstein M, Lill MA, Ernst B. Simulating α/β specificity at the thyroid receptor: Consensus scoring in multidimensional QSAR. ChemMedChem, 2007;2:78-87.
139. Damstra T, Barlow S, Bergman A, Kavlock R, van der Kraak G, editors. Global assessment of the state of the science of endocrine disruptors. Geneva: World Health Organization, 2002, ch. 3.12.5, and references therein.
140. Bandiera S, Sawyer TW, Campbell MA, Fujita T, Safe S. Competitive binding to the cytosolic 2,3,7,8-tetrachlorodibenzo-p-dioxin receptor: Effects of structure on the affinities of substituted halogenated biphenyls-A QSAR analysis. Biochem Pharmacol 1983;32:3803-13.
141. Denomme MA, Homonko K, Fujita T, Sawyer T, Safe S. Substituted polychlorinated dibenzofuran receptor-binding affinities and hydrocarbon hydroxylase induction potenties-A QSAR analysis. Chem Biol Inter 1986;57:175-87.
142. Golas CL, Prokipcak RD, Okey AB, Manchester DK, Safe S, Fujita T. Competitive binding of 7-substituted-2,3-dichlorodibenzo-p-dioxins with human Ah receptor-A QSAR analysis. Biochem Pharmacol 1990;40:737-41.
143. Rannug U, Sjogren M, Rannun A, Gillner M, Toftgard R, Gustafsson JA, et al. Use of artificial intelligence in structure-affinity correlations of 2,3,7,8-tetrachlo-rodibenzo-p-dioxin (TCDD) receptor ligands. Carcinogenesis 1991;11:2007-15.
144. Mekenyan OG, Veith GD, Call DJ, Ankley GT. A QSAR evaluation of Ah receptor binding of halogenated aromatic xenobiotics. Environ Health Perspect 1996;104:1302-10.
145. So SS, Karplus M. 3D-QSAR from molecular similarity matrices and genetic neural networks. J Med Chem 1997;40:4360-71.
146. Waller CL, McKinney JD. Comparative molecular field analysis of polyhaloge-nated dibenzo-p-dioxins, dibenzofurans, and biphenyls. J Med Chem 1992;35:3660-6.
147. Wagener M, Sadowski J, Gasteiger J. Autocorrelation of molecular surface properties for modeling corticosteroid binding globulin and cytosolic Ah receptor activity by neural networks. J Am Chem Soc 1995;117:7769-75.
148. Mhin BJ, Lee JE, Choi W. Understanding the congener-specific toxicity in polychlorinated dibenzo-p-dioxins: Chlorination pattern and molecular quadrupole moment. J Am Chem Soc 2002;124:144-8.
149. γ crystal structure. Toxicology 2002;176:51-7.
150. Mankowski DC, Ekins S. Prediction of human drug metabolizing enzyme induction. Curr Drug Metab 2003;4:381-91.
151. Procopio M, Lahm A, Tramontano A, Pitea D. A model for recognition of polychlorinated dibenzo-p-dioxins by the aryl hydrocarbon receptor. Eur J Biochem 2002;269:13-8.
152. Vedani A, Dobler M, Lill MA. Virtual test kits for predicting harmful effects triggered by drugs and chemicals mediated by specific proteins. ALTEX 2005;22:123-34.
153. Vedani A, Dobler M, Lill MA. The challenge of predicting drug toxicity in silico. Pharmacol Toxicol 2006;99:195-208.
154. Lukacova V, Balaz S. Multimode ligand binding in receptor-site modeling: Implementation CoMFA. J Chem Inf Comput Sci 2003;43:2093-105.
155. Arulmozhiraja A, Morita M. Structure-activity relationships for the toxicity of polychlorinated dibenzofurans: Approach through density functional theory-based descriptors. Chem Res Toxicol 2004;17:348-56.
156. Hirokawa S, Imasaka T, Imasaka T. Chlorine substitution pattern, molecular electronic properties, and the nature of the ligand-receptor interaction: Quantitative property-activity relationships of polychlorinated dibenzofurans. Chem Res Toxicol 2005;18:232-8.
157. Wang Y, Liu H, Zhao C, Liu H, Cai Z, Jiang G. Quantitative structure-activity relationships models for the prediction of the toxicity of polybrominated diphenyl ether congeners. Environ Sci Technol 2005;39:4961-6.
158. Zheng G, Xiao M, Lu XH. QSAR study on the Ah receptor-binding affinities of polyhalogenated dibenzo-p-dioxins using net atomic-charge descriptors and a radial basis neural network. Anal Bioanal Chem 2005;383:810-6.
159. Sovadinova I, Blaha L, Janosek J, Hilscherova K, Giesy JP, Jones PD, et al. Cytotoxicity and aryl hydrocarbon receptor-mediated activity of n-heterocyclic polycyclic aromatic hydrocarbons: Structure-activity relationships. Environ Toxicol Chem 2006;25:1291-7.
160. Benfenati E. (2006, personal communication).
161. Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L. Sydow-Backman M, et al. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci USA 1998;95:12208-13.
162. Blumberg B, Sabbagh W Jr, Juguilon H, Bolado J Jr, van Meter CM, Ong ES, et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev 1998;12:3195-205.
163. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 1998;92:73-82.
164. Staudinger J, Liu Y, Madan A, Habeebu S, Klaassen CD. Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor. Drug Metab Dispos 2001;29:1467-72.
165. El-Sankary W, Gibson GG, Ayrton A, Plant N. Use of a reporter gene assay to predict and rank the potency and efficacy of CYP3A4 inducers. Drug Metab Dispos 2001;29:1499-504.
166. Dussault I, Lin M, Hollister K, Wang EH, Synold TW, Forman BM. A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity. J Biol Chem 2001;276:33309-12.
167. Drocourt L, Pascussi JM, Assenat E, Fabre JM, Maurel P, Vilarem MJ. Calcium channel modulators of the dihydropyridine family are human pregnane X receptor activators and inducers of CYP3A, CYP2B, and CYP2C in human hepato-cytes. Drug Metab Dispos 2001;29:1325-31.
168. Moore JT, Kliewer SA. Use of the nuclear receptor PXR to predict drug interactions. Toxicology 2000;153:1-10.
169. Takeshita A, Koibuchi N, Oka J, Taguchi M, Shishiba Y, Ozawa Y. Bisphenol-A, an environmental estrogen, activates the human orphan nuclear receptor, steroid and xenobiotic receptor-mediated transcription. Eur J Endocrinol 2001;145:513-7.
170. Coumol X, Diry M, Barouki R. PXR-dependent induction of human CYP3A4 gene expression by organochlorine pesticides. Biochem Pharmacol 2002;64:1513-9.
171. Goodwin B, Moore LB, Stoltz CM, McKee DD, Kliewer SA. Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Mol Pharmacol 2001;60:427-31.
172. Synold TW, Dussault I, Forman BM. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nat Med 2001;7:584-90.
173. Stoilov I. Cytochrome P450s: coupling development and environment. Trends Genet 2001;17:629-32.
174. Watkins RE, Wisely GB, Moore LB, Collins JL, Lambert MH, Williams SP, et al. The human nuclear xenobiotic receptor PXR: Structural determinants of directed promiscuity. Science 2001;292:2329-33.
175. Watkins RE, Maglich JM, Moore LB, Wisely GB, Noble SM, Davis-Searles PR, et al. 2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry 2003;42:1430-8.
176. Watkins RE, Davis-Searles PR, Lambert MH, Redinbo MR. Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor. J Mol Biol 2003;331:815-28.
177. Chrencik JE, Orans JO, Moore LB, Xue Y, Peng L, Collins JL, et al. Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin. Mol Endocrinol 2005;19:1125-34.
178. Ekins S, Erickson JA. A pharmacophore for human pregnane X receptor ligands. Drug Metab Dispos 2002;30:96-9.
179. Schuster D, Langer T. The identification of ligand features essential for PXR activation by pharmacophore modeling. J Chem Inf Model 2005;45:431-9.
180. M.N. Jacobs. In silico tools to aid risk assessment of endocrine disrupting chemicals. Toxicology 2004;205:43-53.
181. Ingraham HA, Redinbo MR. Orphan nuclear receptors adopted by crystallography. Curr Opin Struct Biol 2005;15:708-15.
182. Watkins RE, Wisely GB, Moore LB, Collins JL, Lambert MH, Williams SP, et al. The human nuclear xenobiotic receptor PXR: Structural determinants of directed promiscuity. Science 2001;292:2329-33.
183. Huang W, Zhang J, Wei P, Schrader WT, Moore DD. Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR. Mol Endocrinol 2004;18:2402-8.
184. Dussault I, Yoo HD, Lin M, Wang E, Fan M, Batta AK, et al. Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance. Proc Natl Acad Sci USA 2003;100:833-8.
185. Suino K, Peng L, Reynolds R, Li Y, Cha JY, Repa JJ, Kliewer SA, et al. The nuclear xenobiotic receptor CAR: Structural determinants of constitutive activation and heterodimerization. Mol Cell 2004;16:893-905.
186. Shan L, Vincent J, Brunzelle JS, Dussault I, Lin M, Ianculescu I, et al. Structure of the murine constitutive androstane receptor complexed to androstenol: A molecular basis for inverse agonism. Mol Cell 2004;16:907-17.
187. Xu RX, Lambert MH, Wisely BB, Warren EN, Weinert EE, Waitt GM, et al. A structural basis for constitutive activity in the human CAR/RXR alpha heterodimer. Mol Cell 2004;16:919-28.
188. α, and LXRβ. Pharm Res 2002;19:1788-800.
189. Forman BM, Tzameli I, Choi H-S, Chen J, Simha D, Seol W, et al. Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 1998;395:612-5.
190. Usui T, Saitoh Y, Komada F. Induction of CYP3As in HepG2 cells by several drugs. Association between induction of CYP3A4 and expression of glucocorticoid receptor. Biol Pharm Bull 2003;26:510-7.
191. Pascussi JM, Drocourt L, Fabre JM, Maurel P, Vilarem, MJ. Dexamethasone induces pregnane X receptor and retinoid X receptor-alpha expression in human hepatocytes: Synergistic increase of CYP3A4 induction by pregnane X receptor activators. Mol Pharmacol 2000;58:361-72.
192. Pascussi JM, Drocourt L, Gerbal-Chaloin S, Fabre JM, Maurel P, Vilarem MJ. Dual effect of dexamethasone on CYP3A4 gene expression in human hepato-cytes: Sequential role of glucocorticoid receptor and pregnane X receptor. Eur J Biochem 2001;268:6346-58.
193. Pascussi JM, Gerbal-Chaloin S, Fabre JM, Maurel P, Vilarem MJ. Dexametha-sone enhances constitutive androstane receptor expression in human hepatocytes: Consequences on cytochrome P450 gene regulation. Mol Pharmacol 2000;58:1441-50.
194. Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, et al. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 2002;110:93-105.
195. Kauppi B, Jakob C, Farnegardh M, Yang J, Ahola H, Alarcon M, et al. The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism. J Biol Chem 2003;278:22748-54.
196. Lewis DFV, Ioannides C, Parke DV, Schulte-Hermann R. Quantitative structure-activity relationships in a series of endogenous and synthetic steroids exhibiting induction of CYP3A activity and hepatomegaly associated with increased DNA synthesis. J Steroid Biochem Mol Biol 2000;74:179-85.
197. α) LBD: Quantitative structure-activity relationships within a series of CYP3A4 inducers where induction is mediated via hGR involvement. J Steroid Biochem Mol Biol 2002;82:195-9.