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Preparation of Encoded Combinatorial Libraries for Drug Discovery

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Combinatorial Library

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 201))

Abstract

The revolution in genomics and proteomics is projected to expand the number of potential therapeutic targets to between 5,000 and 10,000 from the approximately 500 targets that have historically been used by the pharmaceutical industry in the development of drugs (1,2). The research and development of a safe and effective drug is a slow and expensive process, which is currently estimated to take an average of 12 years and to have a risk adjusted cost of $500 million per drug (3). The pharmaceutical industry is under intense pressure to bring novel drugs to market quickly and cost-effectively. Combinatorial chemistry has emerged during the past decade as a powerful tool to help accelerate the drug discovery process (4–7). Combinatorial chemistry refers to methods for the high-throughput synthesis of a significant number (102 to >106) of compounds (8). Among the various methods developed (9–20), the solidphase split-pool synthesis (21–23) is perhaps the most efficient approach for the rapid synthesis of a large number of compounds. In this approach, a library that usually contains >10,000 members can be constructed very rapidly from a small number of chemical building blocks. Figure 1 illustrates the split-pool synthesis with a two step reaction A + B that uses three building blocks in step 1 (A1, A2, A3) and three building blocks in step 2 (B1, B2, B3). Nine products can be generated using only six reactions.

The split-pool synthesis method.

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References

  1. Edwards A. M., Arrowsmith C. H., and Pallieres B. D. (2000) Proteomics: new tools for a new era. Bridging the gap between genomics and drug discovery. Mod. Drug Disc. Sept, 55–60.

    Google Scholar 

  2. Drews J. (2000) Drug discovery: a historical perspective. Science 287, 1960–1964.

    Article  PubMed  CAS  Google Scholar 

  3. Lipper R. A. (1999) E pluribus product. Mod. Drug Disc. Jan/Feb, 55–60.

    Google Scholar 

  4. Floyd C. D., Leblanc C., and Whittaker M. (1999) Combinatorial chemistry as a tool for drug discovery, in Progress in Medicinal Chemistry (King F. D. and Oxford A. W., eds.), Elsevier Science Amsterdam, Vol. 36, pp. 91–168.

    Google Scholar 

  5. Dolle R. E. (2000) Comprehensive survey of combinatorial library synthesis:1999. J. Comb. Chem. 2, 383–433.

    Article  PubMed  CAS  Google Scholar 

  6. Dolle R. E. and Nelson K. H. J. (1999) Comprehensive survey of combinatorial library synthesis: 1998. J. Comb. Chem. 1, 235–282.

    Article  PubMed  CAS  Google Scholar 

  7. Dolle R. E. (1999) Comprehensive survey of chemical libraries yielding enzyme inhibitors, receptor agonists and antagonists, and other biologically active agents: 1992 through 1997. Annu. Rep. Comb. Chem. Mol. Diversity 2, 93–127.

    CAS  Google Scholar 

  8. Fecik R. A., Frank K. E., Gentry E. J., Menon S. R., Mitscher L. A., and Telikepalli H. (1998) The search for orally active medications through combinatorial chemistry. Med. Res. Rev. 18, 149–185.

    Article  PubMed  CAS  Google Scholar 

  9. Geysen H. M., Meloen R. H., and Barteling S. J. (1984) Use of peptide synthesis to probe viral antigens for epitopes to a resolution of a single amino acid. Proc. Natl. Acad. Sci. USA 81, 3998–4002.

    Article  PubMed  CAS  Google Scholar 

  10. Franzen R. G. (2000) Recent advances in the preparation of heterocycles on solid support: a review of the literature. J. Comb. Chem. 2, 195–214.

    Article  PubMed  CAS  Google Scholar 

  11. Suto M. J. (1999) Developments in solution-phase combinatorial chemistry. Curr. Opin. Drug Disc. Develop. 2, 377–384.

    CAS  Google Scholar 

  12. Parlow J. J., Devraj R. V., and South M. S. (1999) Solution-phase chemical library synthesis using polymer-assisted purification techniques. Curr. Opin. Chem. Biol. 3, 320–336.

    Article  PubMed  CAS  Google Scholar 

  13. Hermkens P., Ottenheijm H., and Rees D. (1996) Solid-phase organic reactions: a review of recent literature. Tetrahedron 52, 4527–4554.

    Article  CAS  Google Scholar 

  14. Hermkens P., Ottenheijm H., and Rees D. (1997) Solid-phase organic reactions II: a review of the literature Nov 95-Nov 96. Tetrahedron 53, 5643–5678.

    Article  CAS  Google Scholar 

  15. Booth S., Hermkens P. H. H., Ottenheijm H. C. J., and Rees D. C. (1998) Solidphase organic reactions III: a review of the literature Nov 96-Dec 97. Tetrahedron 54, 15,385–15,443.

    Article  CAS  Google Scholar 

  16. Früchtel J. S. and Jung G. (1996) Organic chemistry on solid supports. Angew. Chem. Int. Ed. Engl. 35, 17–41.

    Article  Google Scholar 

  17. Osborn H. M. I. and Khan T. H. (1999) Recent developments in polymer supported synthesis of oligosaccharides and glycopeptides. Tetrahedron 55, 1807–1850.

    Article  CAS  Google Scholar 

  18. Lorsbach B. A. and Kurth M. J. (1999) Carbon-carbon bond forming solid-phase reactions. Chem. Rev. 99, 1549–1581.

    Article  PubMed  CAS  Google Scholar 

  19. Gordon K. and Balasubramanian S. (1999) Recent advances in solid-phase chemical methodologies. Curr. Opin. Drug Disc. Develop. 2, 342–349.

    CAS  Google Scholar 

  20. Schreiber S. L. (2000) Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964–1969.

    Article  PubMed  CAS  Google Scholar 

  21. Furka A. (1995) History of combinatorial chemistry. Drug Dev. Res. 36, 1–12.

    Article  CAS  Google Scholar 

  22. Lam K. S., Salmon S. E., Hersh E. M., Hruby V. J., Kazmierski W. M., and Knapp R. J. (1991) A new type of synthetic peptide library for identifying ligandbinding activity. Nature 354, 82–84.

    Article  PubMed  CAS  Google Scholar 

  23. Houghten R. A., Pinilla C., Blondelle S. E., Appel J. R., Dooley C. T., and Cuervo J. H. (1991) Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery. Nature 354, 84–86.

    Article  PubMed  CAS  Google Scholar 

  24. Brenner S. and Lerner R. A. (1992) Encoded combinatorial chemistry. Proc. Natl. Acad. Sci. USA 89, 5381–5383.

    Article  PubMed  CAS  Google Scholar 

  25. Needels M. C., Jones D. G., Tate E. H., Heinkel G. L., Kochersperger L. M., Dower W. J., Barrett R. W., and Gallop M. A. (1993) Generation and screening of an oligonucleotide-encoded synthetic peptide library. Proc. Natl. Acad. Sci. USA 90, 10,700–10,704.

    Article  PubMed  CAS  Google Scholar 

  26. Nielsen J., Brenner S., and Janda K. D. (1993) Synthetic methods for the implementation of encoded combinatorial chemistry. J. Am. Chem. Soc. 115, 9812–9813.

    Article  CAS  Google Scholar 

  27. Kerr J. M., Banville S. C., and Zuckermann R. N. (1993) Encoded combinatorial peptide libraries containing non-natural amino acids. J. Am. Chem. Soc. 115, 2529–2531.

    Article  CAS  Google Scholar 

  28. Nikolaiev V., Stierandova A., Krchnak V., Seligmann B., Lam K. S., Salmon S. E., and Lebl M. (1993) Peptide-encoding for structure determination of nonsequenceable polymers within libraries synthesized and tested on solid-phase supports. Pept. Res. 6, 161–170.

    PubMed  CAS  Google Scholar 

  29. Krchnak V., Wichsel A., Cabel D., and Lebl M. (1995) Linear presentation of variable side-chain spacing in a highly diverse combinatorial library. Pept. Res. 8, 198–205.

    PubMed  CAS  Google Scholar 

  30. Ohlmeyer M. H. J., Swanson R. N., Dillard L., Reader J. C., Asouline G., Kobayashi R., Wigler M., and Still W. C. (1993) Complex synthetic chemical libraries indexed with molecular tags. Proc. Natl. Acad. Sci. USA 90, 10,922–10,926.

    Article  PubMed  CAS  Google Scholar 

  31. Nestler H. P., Bartlett P. A., and Still W. C. (1994) A general method for molecular tagging of encoded combinatorial chemistry libraries. J. Org. Chem. 59, 4723–4724.

    Article  CAS  Google Scholar 

  32. Burbaum J. J., Ohlmeyer M. H. J., Reader J. C., Henderson I., Dillard L. W., Li G., Randle T. L., Sigal N. H., Chelsky D., and Baldwin J. J. (1995) A paradigm for drug discovery employing encoded combinatorial libraries. Proc. Natl. Acad. Sci. USA 92, 6027–6031.

    Article  PubMed  CAS  Google Scholar 

  33. Ni Z.-J., Maclean D., Holmes C. P., Murphy M. M., Ruhland B., Jacobs J. W., Gordon E. M., and Gallop M. A. (1996) Versatile approach to encoding combinatorial organic syntheses using chemically robust secondary amine tags. J. Med. Chem. 39, 1601–1608.

    Article  PubMed  CAS  Google Scholar 

  34. Moran E. J., Sarshar S., Cargill J. F., Shahbaz M. M., Lio A., Mjalli A. M. M., and Armstrong R. W. (1995) Radio frequency tag encoded combinatorial library method for the discovery of tripeptide-substituted cinnamic acid inhibitors of the protein tyrosine phosphatase PTP1B. J. Am. Chem. Soc. 117, 10,787–10,788.

    Article  CAS  Google Scholar 

  35. Nicolaou K. C., Xiao X.-Y., Parandoosh Z., Senyei A., and Nova M. P. (1995) Radiofrequency encoded combinatorial chemistry. Angew. Chem., Int. Ed. Engl. 4, 2289–2291.

    Article  Google Scholar 

  36. Nicolaou K. C., Pfefferkorn J. A., Mitchell H. J., Roecker A. J., Barluenga S., Cao G. Q., Affleck R. L., and Lillig J. E. (2000) Natural product-like combinatorial libraries based on privileged structures. 2. Construction of a 10000-membered benzopyran library by directed split-and-pool chemistry using NanoKans and optical encoding. J. Am. Chem. Soc. 122, 9954–9967.

    Article  CAS  Google Scholar 

  37. Baldwin J. J. and Horlbeck E. (1997) Encoded libraries may be created using split-pool or direct divide synthesis. US Patent 5,663,046.

    Google Scholar 

  38. Lipinski C. A., Lombardo F., Dominy B. W., and Feeney P. J. (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 23, 3–25.

    Article  CAS  Google Scholar 

  39. Egan W. J., Merz K. M., Jr., and Baldwin J. J. (2000) Prediction of drug absorption using multivariate statistics. J. Med. Chem. 43, 3867–3877.

    Article  PubMed  CAS  Google Scholar 

  40. Dolle R. E., Guo J., O’Brien L., Jin Y., Piznik M., Bowman K. J., Li W., Egan W. J., Cavallaro C. L., Roughton A. L., Zhao Q., Reader J. C., Orlowski M., Jacob-Samuel B., and Carroll C. D. (2000) A statistical-based approach to assessing the fidelity of combinatorial libraries encoded with electrophoric molecular tags. Development and application of tag decode-assisted single bead LC/MS analysis. J. Comb. Chem. 2, 716–731.

    Article  PubMed  CAS  Google Scholar 

  41. Baldwin J. J., Burbaum J. J., Chelsky D., Dillard L. W., Henderson I., Li G., Ohlmeyer M. H. J., Randle T. L., and Reader J. C. (1995) Combinatorial libraries encoded with electrophoric tags. Eur. J. Med. Chem. 30, 349s–358s.

    CAS  Google Scholar 

  42. Baldwin J. J. (1996) Design, synthesis and use of binary encoded synthetic chemical libraries. Mol. Diversity 2, 81–88.

    Article  CAS  Google Scholar 

  43. Chabala J. C., Baldwin J. J., Burbaum J. J., Chelsky D., Dilliard L., Henderson I., Li G., Ohlmeyer M. H. J., Randle T. L., Reader J. C., Rokosz L., and Sigal N. H. (1995) Binary encoded small-molecule libraries in drug discovery and optimization. Persp. Drug Disc. Des. 2, 305–318.

    Article  CAS  Google Scholar 

  44. Appell K. C., Chung T. D. Y., Ohlmeyer M. J. H., Sigal N. H., Baldwin J. J., and Chelsky D. (1996) Biological screening of a large combinatorial library. J. Biomol. Screening 1, 27–31.

    Article  CAS  Google Scholar 

  45. Appell K. C., Chung T. D. Y., Solly K. J., and Chelsky D. (1998) Biological characterization of neurokinin antagonists discovered through screening of a combinatorial library. J. Biomol. Screening 3, 19–27.

    Article  CAS  Google Scholar 

  46. Carroll C. D., Patel H., Johnson T. O., Guo T., Orlowski M., He Z.-M., Cavallaro C. L., Guo J., Oksman A., Gluzman I. Y., Connelly J., Chelsky D., Goldberg D. E., and Dolle R. E. (1998) Identification of potent inhibitors of plasmodium falciparum plasmepsin II from an encoded statine combinatorial library. Bioorg. Med. Chem. Lett. 8, 2315–2320.

    Article  PubMed  CAS  Google Scholar 

  47. Horlick R. A., Ohlmeyer M. H., Stroke I. L., Strohl B., Pan G., Schilling A. E., Paradkar V., Quintero J. G., You M., Riviello C., Thorn M. B., Damaj B., Fitzpatrick V. D., Dolle R. E., Webb M. L., Baldwin J. J., and Sigal N. H. (1999) Small molecule antagonists of the bradykinin B1 receptor. Immunopharmacology 43, 169–177.

    Article  PubMed  CAS  Google Scholar 

  48. McMillan K., Adler M., Auld D. S., Baldwin J. J., Blasko E., Browne L. J., Chelsky D., Davey D., Dolle R. E., Eagen K. A., Erickson S., Feldman R. I., Glaser C. B., Mallari C., Morrissey M. M., Ohlmeyer M. H. J., Pan G., Parkinson J. F., Phillips G. B., Polokoff M. A., Sigal N. H., Vergona R., Whitlow M., Young T. A., and Devlin J. J. (2000) Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. Proc. Natl. Acad. Sci. USA 97, 1506–1511.

    Article  PubMed  CAS  Google Scholar 

  49. Li G. and Guo T. (2000) ECLiPS™ technology for drug discovery, in Frontiers of Biotechnology & Pharmaceuticals (eiZhao K., Reiner J., and Chen S.-H., eds.), Science Press New York, Vol. 1, pp. 150–163.

    Google Scholar 

  50. Hobbs D. and Guo T. (2001) Library design concepts and implementation strategies, in Combinatorial Library Design and Evaluation (eiGhose A. K., Viswanadhan and V. N., eds.), Marcel Dekker New York, pp. 1–50.

    Google Scholar 

  51. Dolle R. E., Guo T., Johnson T. O., Patel H. K., Tao S., and He Z. M. (1999) Combinatorial hydroxy-amino acid amide libraries. US Patent 5,972,719.

    Google Scholar 

  52. Guo T. (2000) Encoded combinatorial libraries in drug discovery. 219th ACS National Meeting, San Francisco, March 26–30, 2000, ORGN-218.

    Google Scholar 

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Authors and Affiliations

  1. Pharmacopeia Inc., Princeton, NJ

    Tao Guo & Doug W. Hobbs

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  1. Tao Guo
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  2. Doug W. Hobbs
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Editors and Affiliations

  1. BD Biosciences, San Jose, California

    Lisa Bellavance English

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© 2002 Humana Press Inc.

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Guo, T., Hobbs, D.W. (2002). Preparation of Encoded Combinatorial Libraries for Drug Discovery. In: English, L.B. (eds) Combinatorial Library. Methods in Molecular Biology™, vol 201. Springer, Totowa, NJ. https://doi.org/10.1385/1-59259-285-6:23

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  • DOI: https://doi.org/10.1385/1-59259-285-6:23

  • Publisher Name: Springer, Totowa, NJ

  • Print ISBN: 978-0-89603-980-3

  • Online ISBN: 978-1-59259-285-2

  • eBook Packages: Springer Protocols

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