Table of Contents
Journal of Computational Medicine
Volume 2013, Article ID 513537, 8 pages
http://dx.doi.org/10.1155/2013/513537
Research Article

LASSO-ing Potential Nuclear Receptor Agonists and Antagonists: A New Computational Method for Database Screening

1Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay-Varina, NC 27526, USA
2National Exposure Research Laboratory, US-Environmental Protection Agency, 109 TW Alexander Drive, Research Triangle Park, NC 27711, USA
3SimBioSys, Inc., 135 Queen's Plate Drive, Suite 520, Toronto, ON, Canada M9W 6V1
4Royal Society of Chemistry, 904 Tamaras Circle, Wake Forest, NC 27587, USA

Received 1 February 2013; Accepted 28 May 2013

Academic Editor: Gabriela Mustata Wilson

Copyright © 2013 Sean Ekins et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. G. Smith and G. E. O. Muscat, “Skeletal muscle and nuclear hormone receptors: implications for cardiovascular and metabolic disease,” International Journal of Biochemistry and Cell Biology, vol. 37, no. 10, pp. 2047–2063, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. A. K. Hotchkiss, C. V. Rider, C. R. Blystone et al., “Fifteen years after “wingspread”—environmental endocrine disrupters and human and wildlife health: where we are today and where we need to go,” Toxicological Sciences, vol. 105, no. 2, pp. 235–259, 2008. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Tenbaum and A. Baniahmad, “Nuclear receptors: structure, function and involvement in disease,” International Journal of Biochemistry and Cell Biology, vol. 29, no. 12, pp. 1325–1341, 1997. View at Publisher · View at Google Scholar · View at Scopus
  4. A. Zimber and C. Gespach, “Bile acids and derivatives, their nuclear receptors FXR, PXR and ligands: role in health and disease and their therapeutic potential,” Anti-Cancer Agents in Medicinal Chemistry, vol. 8, no. 5, pp. 540–563, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. P. L. Feldman, M. H. Lambert, and B. R. Henke, “PPAR modulators and PPAR pan agonists for metabolic diseases: the next generation of drugs targeting peroxisome proliferator-activated receptors?” Current Topics in Medicinal Chemistry, vol. 8, no. 9, pp. 728–749, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. X. Ma, J. R. Idle, and F. J. Gonzalez, “The pregnane X receptor: from bench to bedside,” Expert Opinion on Drug Metabolism and Toxicology, vol. 4, no. 7, pp. 895–908, 2008. View at Publisher · View at Google Scholar · View at Scopus
  7. M. Bertolotti, C. Gabbi, C. Anzivino, L. Carulli, P. Loria, and N. Carulli, “Nuclear receptors as potential molecular targets in cholesterol accumulation conditions: insights from evidence on hepatic cholesterol degradation and gallstone disease in humans,” Current Medicinal Chemistry, vol. 15, no. 22, pp. 2271–2284, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. E. E. Baulieu, M. Atger, and M. Best Belpomme, “Steroid hormone receptors,” Vitamins and Hormones, vol. 33, pp. 649–736, 1975. View at Google Scholar · View at Scopus
  9. D. V. Henley and K. S. Korach, “Endocrine-disrupting chemicals use distinct mechanisms of action to modulate endocrine system function,” Endocrinology, vol. 147, no. 6, pp. S25–S32, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. M. D. Krasowski, E. J. Reschly, and S. Ekins, “Intrinsic disorder in nuclear hormone receptors,” Journal of Proteome Research, vol. 7, no. 10, pp. 4359–4372, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. A. C. W. Pike, A. M. Brzozowski, R. E. Hubbard et al., “Structure of the ligand-binding domain of oestrogen receptor beta in the presence of a partial agonist and a full antagonist,” EMBO Journal, vol. 18, no. 17, pp. 4608–4618, 1999. View at Publisher · View at Google Scholar · View at Scopus
  12. A. M. Brzozowski, A. C. W. Pike, Z. Dauter et al., “Molecular basis of agonism and antagonism in the oestrogen receptor,” Nature, vol. 389, no. 6652, pp. 753–758, 1997. View at Publisher · View at Google Scholar · View at Scopus
  13. J. W. R. Schwabe, L. Chapman, J. T. Finch, D. Rhodes, and D. Neuhaus, “DNA recognition by the oestrogen receptor: from solution to the crystal,” Structure, vol. 1, no. 3, pp. 187–204, 1993. View at Google Scholar · View at Scopus
  14. J. S. Sack, K. F. Kish, C. Wang et al., “Crystallographic structures of the ligand-binding domains of the androgen receptor and its T877A mutant complexed with the natural agonist dihydrotestosterone,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 9, pp. 4904–4909, 2001. View at Publisher · View at Google Scholar · View at Scopus
  15. C. E. Bohl, C. Chang, M. L. Mohler et al., “A ligand-based approach to identify quantitative structure-activity relationships for the androgen receptor,” Journal of Medicinal Chemistry, vol. 47, no. 15, pp. 3765–3776, 2004. View at Publisher · View at Google Scholar · View at Scopus
  16. P. L. Shaffer, A. Jivan, D. E. Dollins, F. Claessens, and D. T. Gewirth, “Structural basis of androgen receptor binding to selective androgen response elements,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 14, pp. 4758–4763, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. G. Bertilsson, J. Heidrich, K. Svensson et al., “Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 21, pp. 12208–12213, 1998. View at Publisher · View at Google Scholar · View at Scopus
  18. B. Blumberg, W. Sabbagh Jr., H. Juguilon et al., “SXR, a novel steroid and xenobiotic-sensing nuclear receptor,” Genes and Development, vol. 12, no. 20, pp. 3195–3205, 1998. View at Google Scholar · View at Scopus
  19. S. A. Kliewer, J. T. Moore, L. Wade et al., “An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway,” Cell, vol. 92, no. 1, pp. 73–82, 1998. View at Publisher · View at Google Scholar · View at Scopus
  20. S. Verma, M. M. Tabb, and B. Blumberg, “Activation of the steroid and xenobiotic receptor, SXR, induces apoptosis in breast cancer cells,” BMC Cancer, vol. 9, article 3, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. D. Gupta, M. Venkatesh, H. Wang et al., “Expanding the roles for pregnane X receptor in cancer: proliferation and drug resistance in ovarian cancer,” Clinical Cancer Research, vol. 14, no. 17, pp. 5332–5340, 2008. View at Publisher · View at Google Scholar · View at Scopus
  22. J. Zhou, M. Liu, Y. Zhai, and W. Xie, “The antiapoptotic role of pregnane X receptor in human colon cancer cells,” Molecular Endocrinology, vol. 22, no. 4, pp. 868–880, 2008. View at Publisher · View at Google Scholar · View at Scopus
  23. A. Biswas, S. Mani, M. R. Redinbo et al., “Elucidating the ‘Jekyll and Hyde’ nature of PXR: the case for discovering antagonists,” Pharmaceutical Research, vol. 26, no. 8, pp. 1807–1815, 2009. View at Publisher · View at Google Scholar
  24. B. L. Urquhart, R. G. Tirona, and R. B. Kim, “Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs,” Journal of Clinical Pharmacology, vol. 47, no. 5, pp. 566–578, 2007. View at Publisher · View at Google Scholar · View at Scopus
  25. S. Ekins, S. Kortagere, M. Iyer et al., “Challenges predicting ligand-receptor interactions of promiscuous proteins: the nuclear receptor PXR,” PLoS Computational Biology, vol. 5, no. 12, Article ID e1000594, 2009. View at Publisher · View at Google Scholar · View at Scopus
  26. N. Ai, R. K. DeLisle, S. J. Yu, and W. J. Welsh, “Computational models for predicting the binding affinities of ligands for the wild-type androgen receptor and a mutated variant associated with human prostate cancer,” Chemical Research in Toxicology, vol. 16, no. 12, pp. 1652–1660, 2003. View at Publisher · View at Google Scholar · View at Scopus
  27. M. N. Jacobs, “In silico tools to aid risk assessment of endocrine disrupting chemicals,” Toxicology, vol. 205, no. 1-2, pp. 43–53, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. W. Tong, R. Perkins, L. Xing, W. J. Welsh, and D. M. Sheehan, “QSAR models for binding of estrogenic compounds to estrogen receptor α and β subtypes,” Endocrinology, vol. 138, no. 9, pp. 4022–4025, 1997. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Ekins, L. Mirny, and E. G. Schuetz, “A ligand-based approach to understanding selectivity of nuclear hormone receptors PXR, CAR, FXR, LXRα, and LXRβ,” Pharmaceutical Research, vol. 19, no. 12, pp. 1788–1800, 2002. View at Publisher · View at Google Scholar · View at Scopus
  30. T. Z. Bao, G.-Z. Han, J.-Y. Shim, Y. Wen, and X.-R. Jiang, “Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor α and β subtypes: insights into the structural determinants favoring a differential subtype binding,” Endocrinology, vol. 147, no. 9, pp. 4132–4150, 2006. View at Publisher · View at Google Scholar · View at Scopus
  31. D. Plewczynski, M. Von Grotthuss, S. A. H. Spieser et al., “Target specific compound identification using a support vector machine,” Combinatorial Chemistry and High Throughput Screening, vol. 10, no. 3, pp. 189–196, 2007. View at Publisher · View at Google Scholar · View at Scopus
  32. L. Zhao and R. D. Brinton, “Structure-based virtual screening for plant-based EBβ-selective ligands as potential preventative therapy against age-related neurodegenerative diseases,” Journal of Medicinal Chemistry, vol. 48, no. 10, pp. 3463–3466, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. W. H. Bisson, A. V. Cheltsov, N. Bruey-Sedano et al., “Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 29, pp. 11927–11932, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. S. Laws et al., DSSTox EPA Estrogen Receptor Ki Binding Study (Laws et al.) Database—(KIERBL): SDF file and documentation. 2009 http://www.epa.gov/ncct/dsstox/sdf_kierbl.html.
  35. S. C. Laws, S. Yavanhxay, R. L. Cooper, and J. C. Eldridge, “Nature of the binding interaction for 50 structurally diverse chemicals with rat estrogen receptors,” Toxicological Sciences, vol. 94, no. 1, pp. 46–56, 2006. View at Publisher · View at Google Scholar · View at Scopus
  36. J. R. Rabinowitz, S. B. Little, S. C. Laws, and M.-R. Goldsmith, “Molecular modeling for screening environmental chemicals for estrogenicity: use of the toxicant-target approach,” Chemical Research in Toxicology, vol. 22, no. 9, pp. 1594–1602, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. H. Fang, W. Tong, W. S. Branham et al., “Study of 202 natural, synthetic, and environmental chemicals for binding to the androgen receptor,” Chemical Research in Toxicology, vol. 16, no. 10, pp. 1338–1358, 2003. View at Publisher · View at Google Scholar
  38. D. Ding, L. Xu, H. Fang et al., “The EDKB: an established knowledge base for endocrine disrupting chemicals,” BMC Bioinformatics, vol. 11, no. 6, article 5, 2010. View at Publisher · View at Google Scholar · View at Scopus
  39. R. E. Watkins, P. R. Davis-Searles, M. H. Lambert, and M. R. Redinbo, “Coactivator binding promotes the specific interaction between ligand and the pregnane X receptor,” Journal of Molecular Biology, vol. 331, no. 4, pp. 815–828, 2003. View at Publisher · View at Google Scholar · View at Scopus
  40. R. E. Watkins, J. M. Maglich, L. B. Moore et al., “2.1 Å crystal structure of human PXR in complex with the St. John's wort compound hyperforin,” Biochemistry, vol. 42, no. 6, pp. 1430–1438, 2003. View at Publisher · View at Google Scholar · View at Scopus
  41. Y. Xue, E. Chao, W. J. Zuercher, T. M. Willson, J. L. Collins, and M. R. Redinbo, “Crystal structure of the PXR-T1317 complex provides a scaffold to examine the potential for receptor antagonism,” Bioorganic and Medicinal Chemistry, vol. 15, no. 5, pp. 2156–2166, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. J. E. Chrencik, J. Orans, L. B. Moore et al., “Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin,” Molecular Endocrinology, vol. 19, no. 5, pp. 1125–1134, 2005. View at Publisher · View at Google Scholar · View at Scopus
  43. D. G. Teotico, J. J. Bischof, L. Peng, S. A. Kliewer, and M. R. Redinbo, “Structural basis of human pregnane X receptor activation by the hops constituent colupulone,” Molecular Pharmacology, vol. 74, no. 6, pp. 1512–1520, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. R. E. Watkins, G. B. Wisely, L. B. Moore et al., “The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity,” Science, vol. 292, no. 5525, pp. 2329–2333, 2001. View at Publisher · View at Google Scholar · View at Scopus
  45. Y. Xue, L. B. Moore, J. Orans et al., “Crystal structure of the pregnane X receptor-estradiol complex provides insights into endobiotic recognition,” Molecular Endocrinology, vol. 21, no. 5, pp. 1028–1038, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. K. Bachmann, H. Patel, Z. Batayneh et al., “PXR and the regulation of apoA1 and HDL-cholesterol in rodents,” Pharmacological Research, vol. 50, no. 3, pp. 237–246, 2004. View at Publisher · View at Google Scholar · View at Scopus
  47. S. Ekins, C. Chang, S. Mani et al., “Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites,” Molecular Pharmacology, vol. 72, no. 3, pp. 592–603, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. S. Ekins and J. A. Erickson, “A pharmacophore for human pregnane X receptor ligands,” Drug Metabolism and Disposition, vol. 30, no. 1, pp. 96–99, 2002. View at Publisher · View at Google Scholar · View at Scopus
  49. D. Schuster and T. Langer, “The identification of ligand features essential for PXR activation by pharmacophore modeling,” Journal of Chemical Information and Modeling, vol. 45, no. 2, pp. 431–439, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. K. Yasuda, A. Ranade, R. Venkataramanan et al., “A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine,” Drug Metabolism and Disposition, vol. 36, no. 8, pp. 1689–1697, 2008. View at Publisher · View at Google Scholar · View at Scopus
  51. A. Khandelwal, M. D. Krasowski, E. J. Reschly, M. W. Sinz, P. W. Swaan, and S. Ekins, “Machine learning methods and docking for predicting human pregnane X receptor activation,” Chemical Research in Toxicology, vol. 21, no. 7, pp. 1457–1467, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. S. Kortagere, D. Chekmarev, W. J. Welsh, and S. Ekins, “Hybrid scoring and classification approaches to predict human pregnane X receptor activators,” Pharmaceutical Research, vol. 26, no. 4, pp. 1001–1011, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. S. Ekins, E. J. Reschly, L. R. Hagey, and M. D. Krasowski, “Evolution of pharmacologic specificity in the pregnane X receptor,” BMC Evolutionary Biology, vol. 8, no. 1, article 103, 2008. View at Publisher · View at Google Scholar · View at Scopus
  54. S. Kortagere, D. Chekmarev, W. J. Welsh, and S. Ekins, “Hybrid scoring and classification approaches to predict human pregnane X receptor activators,” Pharmaceutical Research, vol. 26, no. 4, pp. 1001–1011, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. S. Kortagere, M. D. Krasowski, E. J. Reschly, M. Venkatesh, S. Mani, and S. Ekins, “Evaluation of computational docking to identify pregnane X receptor agonists in the toxcast database,” Environmental Health Perspectives, vol. 118, no. 10, pp. 1412–1417, 2010. View at Publisher · View at Google Scholar · View at Scopus
  56. A. Khandelwal, M. D. Krasowski, E. J. Reschly, M. W. Sinz, P. W. Swaan, and S. Ekins, “Machine learning methods and docking for predicting human pregnane X receptor activation,” Chemical Research in Toxicology, vol. 21, no. 7, pp. 1457–1467, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Kortagere and S. Ekins, “Troubleshooting computational methods in drug discovery,” Journal of Pharmacological and Toxicological Methods, vol. 61, no. 2, pp. 67–75, 2010. View at Publisher · View at Google Scholar · View at Scopus
  58. N. Ai, M. D. Krasowski, W. J. Welsh, and S. Ekins, “Understanding nuclear receptors using computational methods,” Drug Discovery Today, vol. 14, no. 9-10, pp. 486–494, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. D. Reid, B. S. Sadjad, Z. Zsoldos, and A. Simon, “LASSO—ligand activity by surface similarity order: a new tool for ligand based virtual screening,” Journal of Computer-Aided Molecular Design, vol. 22, no. 6-7, pp. 479–487, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. N. Huang, B. K. Shoichet, and J. J. Irwin, “Benchmarking sets for molecular docking,” Journal of Medicinal Chemistry, vol. 49, no. 23, pp. 6789–6801, 2006. View at Publisher · View at Google Scholar · View at Scopus
  61. C. Y. Ung, H. Li, C. W. Yap, and Y. Z. Chen, “In silico prediction of pregnane X receptor activators by machine learning approaches,” Molecular Pharmacology, vol. 71, no. 1, pp. 158–168, 2007. View at Publisher · View at Google Scholar · View at Scopus
  62. D. Weininger, “SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules,” Journal of Chemical Information and Computer Sciences, vol. 28, pp. 31–36, 1988. View at Google Scholar · View at Scopus
  63. G. B. McGaughey, R. P. Sheridan, C. I. Bayly et al., “Comparison of topological, shape, and docking methods in virtual screening,” Journal of Chemical Information and Modeling, vol. 47, no. 4, pp. 1504–1519, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. L. R. Murthy, M. P. Johnson, and D. R. Rowley, “Characterization of steroid receptors in human prostate using mibolerone,” Prostate, vol. 8, no. 3, pp. 241–253, 1986. View at Google Scholar · View at Scopus
  65. A. M. Voutchkova, T. G. Osimitz, and P. T. Anastas, “Toward a comprehensive molecular design framework for reduced hazard,” Chemical Reviews, vol. 110, no. 10, pp. 5845–5882, 2010. View at Publisher · View at Google Scholar · View at Scopus