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Chemical Library Design pp 91–109Cite as

Application of Free–Wilson Selectivity Analysis for Combinatorial Library Design

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 685))

Abstract

In this chapter we present an application of in silico quantitative structure–activity relationship (QSAR) models to establish a new ligand-based computational approach for generating virtual libraries. The Free–Wilson methodology was applied to extract rules from two data sets containing compounds which were screened against either kinase or PDE gene family panels. The rules were used to make predictions for all compounds enumerated from their respective virtual libraries. We also demonstrate the construction of R-group selectivity profiles by deriving activity contributions against each protein target using the QSAR models. Such selectivity profiles were used together with protein structural information from X-ray data to provide a better understanding of the subtle selectivity relationships between kinase and PDE family members.

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References

  1. Manning, G., Whyte, D. B., Martinez, R., Hunter, T., Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science 298, 1912–1934.

    Article  PubMed  CAS  Google Scholar 

  2. Kostich, M., English, J., Madison, V., et al. (2002) Human members of the eukaryotic protein kinase family. Genome Biol 3(9), 0043.1–0043.12.

    Article  Google Scholar 

  3. Johnson, L. N., Lewis, R. J. (2001) Structural basis for control by phosphorylation. Chem Rev 101, 2209–2242.

    Article  PubMed  CAS  Google Scholar 

  4. Nagar, B., Bornmann, W. G., Pellicena, P., et al. (2002) Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and Imatinib (STI-571). Cancer Res 62, 4236–4243.

    Google Scholar 

  5. George, S. (2007) Sunitinib, a multitargeted tyrosine kinase inhibitor, in the management of gastrointestinal stromal tumor. Curr Oncol Rep 9(4), 323–327.

    Article  PubMed  CAS  Google Scholar 

  6. Yun, C. -H., Boggon, T. J., Li, Y., et al. (2007) Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 11(3), 217–227.

    Article  PubMed  CAS  Google Scholar 

  7. Stamos, J., Sliwkowski, M. X., Eigenbrot, C. (2002) Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 277(48), 46265–46272.

    Article  PubMed  CAS  Google Scholar 

  8. Fabian, M. A., Biggs, W. H., Treiber, D. K., et al. (2005) A small molecule–kinase interaction map for clinical kinase inhibitors. Nat Biotech 23(3), 329–336.

    Article  CAS  Google Scholar 

  9. Beavo, J. A. (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiologic Rev 75(4), 725–748.

    CAS  Google Scholar 

  10. Soderling, S. H., Beavo, J. A. (2000) Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr Opin Cell Biol 12(2), 174–179.

    Article  PubMed  CAS  Google Scholar 

  11. Manallack, D. T., Hughes, R. A., Thompson, P. E. (2005) The next generation of phosphodiesterase inhibitors: structural clues to ligand and substrate selectivity of phosphodiesterases. J Med Chem 48(10), 3449–3462.

    Article  PubMed  CAS  Google Scholar 

  12. Conti, M., Jin, S. L. (1999) The molecular biology of cyclic nucleotide phosphodiesterases. Prog Nucleic Acid Res Mol Biol 63, 1–38.

    Article  PubMed  CAS  Google Scholar 

  13. Mehats, C., Andersen, C. B., Filopanti, M., Jin, S. L. C., Conti, M. (2002) Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling. Trends Endocrinol Metab 13(1), 29–35.

    Article  PubMed  CAS  Google Scholar 

  14. Perry, M. J., Higgs, G. A. (1998) Chemotherapeutic potential of phosphodiesterase inhibitors. Curr Opin Chem Biol 2(4), 472–481.

    Article  PubMed  CAS  Google Scholar 

  15. Torphy, T. (1998) Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 157, 351.

    PubMed  CAS  Google Scholar 

  16. Rotella, D. P. (2002) Phosphodiesterase 5 inhibitors: current status and potential applications. Nat Rev Drug Discov 1(9), 674–682.

    Article  PubMed  CAS  Google Scholar 

  17. Conti, M., Nemoz, G., Sette, C., Vicini, E. (1995) Recent progress in understanding the hormonal regulation of phosphodiesterases. Endocr Rev 16(3), 370–389.

    PubMed  CAS  Google Scholar 

  18. Weishaar, R. E., Cain, M. H., Bristol, J. A. (1985) A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity. J Med Chem 28(5), 537–545.

    Article  PubMed  CAS  Google Scholar 

  19. Appleman, M. M., Thompson, W. J. (1971) Multiple cyclic nucleotide phosphodiesterase activities from rat brain. Biochemistry 10(2), 311–316.

    Article  PubMed  CAS  Google Scholar 

  20. Manganiello, V. C., Degerman, E. (1999) Cyclic nucleotide phosphodiesterases (PDEs): diverse regulators of cyclic nucleotide signals and inviting molecular targets for novel therapeutic agents. Thromb Haemostasis 82, 407.

    CAS  Google Scholar 

  21. Houslay, M. D., Adams, D. R. (2003) PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J 370, 1.

    Article  PubMed  CAS  Google Scholar 

  22. Corbin, J. D., Francis, S. H. (1999) Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem 274, 13729–13732. doi:10.1074/jbc.274.20.13729.

    Article  PubMed  CAS  Google Scholar 

  23. Francis, S. H. T. I., Corbin, J. D. (2001) Cyclic nucleotide phosphodiesterases: relating structure and function. Prog Nucleic Acid Res Mol Biol 65, 1.

    Article  PubMed  CAS  Google Scholar 

  24. Conti, M., Richter, W., Mehats, C., Livera, G., Park, J. Y. (2003) Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J Biol Chem 278, 5493.

    Article  PubMed  CAS  Google Scholar 

  25. Card, A., Caldwell, C., Min, H., et al. (2009) High-throughput biochemical kinase selectivity assays: panel development and screening applications. J Biomol Screen 14(1), 31–42.

    Article  PubMed  CAS  Google Scholar 

  26. Free, S. M., Wilson, J. W. (1964) A mathematical contribution to structure-activity studies. J Med Chem 7(4), 395–399.

    Google Scholar 

  27. Craig, P. N. (1972) Structure-activity correlations of antimalarial compounds. 1. Free-Wilson analysis of 2-phenylquinoline-4-carbinols. J Med Chem 15(2), 144–149.

    Google Scholar 

  28. Nisato, D., Wagnon, J., Callet, G., et al. (1987) Renin inhibitors. Free-Wilson and correlation analysis of the inhibitory potency of a series of pepstatin analogs on plasma renin. J Med Chem 30(12), 2287–2291.

    Google Scholar 

  29. Schaad, L. J., Hess, B. A., Purcell, W. P., Cammarata, A., Franke, R., Kubinyi, H. (1981) Compatibility of the Free-Wilson and Hansch quantitative structure-activity relations. J Med Chem 24(7), 900–901.

    Google Scholar 

  30. Tomic, S., Nilsson, L., Wade, R. C. (2000) Nuclear receptor-DNA binding specificity: a COMBINE and Free-Wilson QSAR analysis. J Med Chem 43(9), 1780–1792.

    Google Scholar 

  31. Fujita, T., Ban, T. (1971) Structure-activity study of phenethylamines as substrates of biosynthetic enzymes of sympathetic transmitters. J Med Chem 14(2), 148–152.

    Google Scholar 

  32. Hernandez-Gallegos, Z., Lehmann, P. A. (1990) A Free-Wilson/Fujita-Ban analysis and prediction of the analgesic potency of some 3-hydroxy- and 3-methoxy-N-alkylmorphinan-6-one opioids. J Med Chem 33(10), 2813–2817.

    Google Scholar 

  33. Kubinyi, H., Kehrhahn, O. H. (1976) Quantitative structure-activity relationships. 1. The modified Free-Wilson approach. J Med Chem 19(5), 578–586.

    Google Scholar 

  34. Kubinyi, H., Kehrhahn, O. H. (1976) Quantitative structure-activity relationships. 3. A comparison of different Free-Wilson models. J Med Chem 19(8), 1040–1049.

    Google Scholar 

  35. Ekins, S., Gao, F., Johnson, D. L., Kelly, K. G., Meyer, R. D. inventors (2001) Single point interaction screen to predict IC50 patent EP 1 139 267 A2.26.03.2001.

    Google Scholar 

  36. Sciabola, S., Stanton, R. V., Wittkopp, S., et al. (2008) Predicting kinase selectivity profiles using Free-Wilson QSAR analysis. J Chem Inform Model 48(9), 1851–1867.

    Article  CAS  Google Scholar 

  37. Rogers, D., Brown, R. D., Hahn, M. (2005) Using extended-connectivity fingerprints with Laplacian-modified Bayesian analysis in high-throughput screening follow-up. J Biomol Screeni 10, 682–686. First published on September 16, 2005 doi:10.1177/ 1087057105281365.

    Google Scholar 

  38. Durant, J. L., Leland, B. A., Henry, D. R., Nourse, J. G. (2002) Reoptimization of MDL keys for use in drug discovery. J Chem Inform Comput Sci 42(6), 1273–1280.

    Article  CAS  Google Scholar 

  39. Wittkopp, S., Penzotti, J. E., Stanton, R. V., Wildman, S. A. (2007) Knowledge-based docking for kinases with minimal bias. In: 234th ACS National Meeting, Boston, MA, United States.

    Google Scholar 

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Acknowledgment

This chapter is adapted in part with permission from Simone Sciabola et al. (2008) J Chem Info Model 48, 1851–1867. Copyright 2008 American Chemical Society.

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Authors and Affiliations

  1. Pfizer Research Technology Center, Cambridge, MA, USA

    Simone Sciabola, Robert V. Stanton, Theresa L. Johnson & Hualin Xi

Authors
  1. Simone Sciabola
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  2. Robert V. Stanton
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  3. Theresa L. Johnson
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  4. Hualin Xi
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Correspondence to Simone Sciabola .

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Editors and Affiliations

  1. , Department of Pharmacology, University of California, La Jolla, 92093, California, USA

    Joe Zhongxiang Zhou

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Sciabola, S., Stanton, R.V., Johnson, T.L., Xi, H. (2011). Application of Free–Wilson Selectivity Analysis for Combinatorial Library Design. In: Zhou, J. (eds) Chemical Library Design. Methods in Molecular Biology, vol 685. Humana Press. https://doi.org/10.1007/978-1-60761-931-4_5

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  • DOI: https://doi.org/10.1007/978-1-60761-931-4_5

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  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60761-930-7

  • Online ISBN: 978-1-60761-931-4

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