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Design of Screening Collections for Successful Fragment-Based Lead Discovery

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Chemical Library Design

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

Abstract

A successful fragment-based lead discovery (FBLD) campaign largely depends on the content of the fragment collection being screened. To design a successful fragment collection, several factors must be considered, including collection size, property filters, hit follow-up considerations, and screening methods. In this chapter, we will discuss each factor and how it was applied to the design and assembly of one or more fragment collections in a major pharmaceutical company setting. We will also present examples and statistics of screening results from such collections and how subsequent collections can be improved. Lastly, we will provide a summary comparison of selected fragment collections from literature.

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References

  1. Congreve, M., Chessari, C., Tisi, D., Woodhead, A. (2008) Recent advances in fragment-based drug discovery. J Med Chem 51, 3661–3680.

    Article  PubMed  CAS  Google Scholar 

  2. Hesterkamp, T., Whittaker, M. (2008) Fragment-based activity space: smaller is better. Curr Opin Chem Biol 12, 260–268.

    Article  PubMed  CAS  Google Scholar 

  3. Hajduk, P. J., Greer, J. (2007) A decade of fragment-based drug design: strategic advances and lessons learned. Nat Rev Drug Discov 6, 211–219.

    Article  PubMed  CAS  Google Scholar 

  4. Albert, J. S., Blomberg, N., Breeze, A. L., Brown, A. J. H., Burrows, J. N., Edwards, P. D., Folmer, R. H. A., Geschwindner, S., Griffen, E. J., Kenny, P. W., Nowak, T., Olsson, L. -L., Sanganee, H., Shapiro, A. B. (2007) An integrated approach to fragment-based lead generation philosophy, strategy and case studies from AstraZeneca’s drug discovery programmes. Curr Top Med Chem 7, 1600–1629.

    Article  PubMed  CAS  Google Scholar 

  5. Shuker, S. B., Hajduk, P. J., Meadows, R. P., Fesik, S. W. (1996) Discovering high-affinity ligands for proteins: SAR by NMR. Science 274, 1531–1534.

    Article  PubMed  CAS  Google Scholar 

  6. de Kloe, G. E., Bailey, D., Leurs, R., de Esch, I. J. P. (2009) Transforming fragments into candidates: small becomes big in medicinal chemistry. Drug Discovery Today 14, 630–646.

    Article  PubMed  Google Scholar 

  7. Hann, M. M., Oprea, T. I. (2004) Pursuing the lead-likeness concept in pharmaceutical research. Curr Opin Chem Biol, 8, 255–263

    Article  PubMed  CAS  Google Scholar 

  8. Blomberg, N., Cosgrove, D. A., Kenny, P. W., Kolmodin, K. (2009) Design of compound libraries for fragment screening. J Comput Aided Mol Des 23, 513–525.

    Article  CAS  Google Scholar 

  9. Barker, J., Courtney, S., Hesterkamp, T., Ullmann, D., Whittaker, M. (2005) Fragment screening by biochemical assay. Exp Opin Drug Discov 1, 225–236.

    Article  Google Scholar 

  10. Schuffenhauer, A., Ruedisser, S., Marzinzik, A., Jahnke, W., Selzer, P., Jacoby, E. (2005) Library design for fragment based screening. Curr Top Med Chem 5, 751–762.

    Article  PubMed  CAS  Google Scholar 

  11. Fejzo, J., Lepre, C. A., Peng, J. W., Bemis, G. W., Ajay, Murcko, M. A., Moore, J. M. (1999) The SHAPES strategy: an NMR-based approach for lead generation in drug discovery. Chem Biol 6, 755–769.

    Article  PubMed  CAS  Google Scholar 

  12. Lepre, C. A. (2001) Library design for NMR-based screening. Drug Discov Today 6, 133–140.

    Article  PubMed  CAS  Google Scholar 

  13. Taskinen, J. Norinder, U. (2006) In silico predictions of solubility, Comprehen Med Chem II, edited by Taylor, J. B., Triggle, D. J. 5, 627–648.

    Google Scholar 

  14. Congreve, M., Carr, R., Murray, C., Jhoti, H. (2003) A ‘rule of three’ for fragment-based lead discovery. Drug Discov Today 8, 876–877.

    Article  PubMed  Google Scholar 

  15. Mayer, M., Meyer, B. (1999) Characterization of ligand binding by saturation transfer difference NMR spectroscopy. Angew Chem Int Ed 38, 1784–1788.

    Article  CAS  Google Scholar 

  16. Wang, Y., Liu, D., Wyss, D. F. (2004) Competition STD NMR for the detection of high-affinity ligands and NMR-based screening. Magn Reson Chem 42, 485–489.

    Article  PubMed  CAS  Google Scholar 

  17. Dalvit, C., Pevarello, P., Tato, M., Vulpetti, A., Sundstrom, M. (2000) Identification of compounds with binding affinity to proteins via magnetization transfer from bulk water. J Biomol NMR 18, 65–68.

    Article  PubMed  CAS  Google Scholar 

  18. Baurin, N., Aboul-Ela, F., Barril, X., Davis, B., Drysdale, M., Dymock, B., Finch, H., Fromont, C., Richardson, C., Simmonite, H., Hubbard, R. E. (2004) Design and characterization of libraries of molecular fragments for use in NMR screening against protein targets. J Chem Inf Comput Sci 44, 2157–2166.

    Article  PubMed  CAS  Google Scholar 

  19. Hajduk, P. J., Huth, J., Tse, C. (2005) Predicting protein druggability. Drug Discov Today 10, 1675–1682.

    Article  PubMed  CAS  Google Scholar 

  20. Lau, W. F., Hepworth, D., Magee, T. V., Du, J., Bakken, G. A., Miller, M. D., Hendsch, Z. S., Thanabal, V., Kolodziej, S. A., Xing, L., Hu, Q., Narasimhan, L. S., Love, R., Charlton, M. E., Hughes, S., Van Hoorn, W., Mills, J. E., Withka, J. M. (2010) Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics. J Comput-Aided Mol Des. Manuscript in preparation.

    Google Scholar 

  21. Hu, Q., Yan, J., Withka, J. M., Sahasrabudhe, P., Moore, C., Na, J., Narasimhan, L. S. (2009) Computational analysis on NMR screenings of the Pfizer Fragment Initiative collection. 238th ACS National Meeting, Washington, DC, United States.

    Google Scholar 

  22. Hopkins, A. L., Groom, C. R., Alex, A. (2004) A useful metric for lead selection. Drug Disc Today 9, 430–431.

    Article  Google Scholar 

  23. Huuskonen, J., Rantanen, J., Livingstone, D. (2000) Prediction of aqueous solubility for a diverse set of organic compounds based on atom-type electrotopological state indices. Eur J Med Chem 35, 1081–1088.

    Article  PubMed  CAS  Google Scholar 

  24. Chemical Computing Group Inc., Montreal, H3A 2R7 Canada.

    Google Scholar 

  25. Baurin, N., Baker, R., Richardson, C., Chen, I., Foloppe, N., Potter, A., Jordan, A., Roughley, S., Parratt, M., Greaney, P., Morley, D., Hubbard, R. E. (2004) Drug-like annotation and duplicate analysis of a 23-supplier chemical database totalling 2.7 million compounds. J Chem Inf Comput Sci 44, 643–651.

    Article  PubMed  CAS  Google Scholar 

  26. Siegal, G., Ab, E., Schultz, J. (2007) Integration of fragment screening and library design. Drug Discov Today 12, 1032–1039

    Article  PubMed  CAS  Google Scholar 

  27. Chen, I., Hubbard, R. E. (2009) Lessons for fragment library design: analysis of output from multiple screening campaigns. J Comput Aided Mol Des 23, 603–620.

    Article  Google Scholar 

  28. Hubbard, R. E., Davis, B., Chen, I., Drysdale, M. (2007) The SeeDs approach: integrating fragments into drug discovery. Curr Top Med Chem 7, 1568–1581.

    Article  PubMed  CAS  Google Scholar 

  29. Meiboom, S., Gill, D. (1958) Modified spin-echo method for measuring nuclear relaxation times. Rev Sci Instrum 29, 688–691.

    Article  CAS  Google Scholar 

  30. Hajduk, P. J., Huth, J. R., Fesik, S. (2005) Druggability indices for protein targets. J Med Chem 48, 2518–2525.

    Article  PubMed  CAS  Google Scholar 

  31. Halgren, T. A. (2009) Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model 49, 377–389.

    Article  PubMed  CAS  Google Scholar 

  32. Ruppert, J., Welch, W., Jain, A. N. (1997) Automatic identification and representation of protein binding sites for molecular docking. Prot Sci 6, 524–533.

    Article  CAS  Google Scholar 

  33. Brewer, M., Ichihara, O., Kirchhoff, C., Schade, M., Whittaker, M. (2008) Assembling a fragment library. Fragment-Based Drug Discovery: A Practical Approach, in (Zartler, E., Shapiro, M. J. eds.), pp. 39–62.

    Google Scholar 

  34. Hartshorn, M. J., Murray, C. W., Cleasby, A., Frederickson, M., Tickle, I. J., Jhoti, H. (2005) Fragment-based lead discovery using X-ray crystallography. J Med Chem 48, 403–413.

    Article  PubMed  CAS  Google Scholar 

  35. Card, G.L., Blasdel, L., England, B. P., Zhang, C., Suzuki, Y., Gillette, S., Fong, D., Ibrahim, P. N., Artis, D. R., Bollag, G., Milburn, M. V., Kim, S., Schlessinger, J., Zhang, K. Y. J. (2005) A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design. Nat Biotechnol 23, 201–207.

    Article  PubMed  CAS  Google Scholar 

  36. Blaney, J., Nienaber, V., Burley, S. K. (2006) Fragment-based lead discovery and optimization using X-ray crystallography, computational chemistry, and highthroughput organic synthesis, Fragment-Based Approaches in Drug Discovery, in (Jahnke, W., Erlanson, D. A., Mannhold, R., Kubinyi, H., and Folkers, G., eds.), pp. 215–248.

    Google Scholar 

  37. Erlanson, D.A., Ballinger, M. D., Wells, J. A. (2006) Tethering, Fragment-Based Approaches in Drug Discovery, in (Jahnke, W., Erlanson, D. A., Mannhold, R., Kubinyi, H., and Folkers, G., eds.), pp. 285–312.

    Google Scholar 

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Acknowledgments

We would like to thank Drs. Ben Burke and Zhongxiang (Joe) Zhou for their valuable comments and insights throughout the preparation of this manuscript.

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Authors and Affiliations

  1. Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA, USA

    James Na & Qiyue Hu

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  1. James Na
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  2. Qiyue Hu
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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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Na, J., Hu, Q. (2011). Design of Screening Collections for Successful Fragment-Based Lead Discovery. 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_11

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  • DOI: https://doi.org/10.1007/978-1-60761-931-4_11

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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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