Molecular Diversity

, Volume 2, Issue 1–2, pp 81–88 | Cite as

Design, synthesis and use of binary encoded synthetic chemical libraries

  • John J. Baldwin
Research Papers


With the advent of combinatorial chemistry a new paradigm is evolving in the field of drug discovery. The approach is based on an integration of chemistry, high-throughput screening and automation engineering. The chemistry arm is usually based on solid-phase synthesis technology as the preferred approach to library construction. One of the most powerful of the solid-phase methods is encoded split synthesis, in which the reaction history experience by each polymeric bead is unambiguously recorded. This split-and-pool approach, employing chemically robust tags, was used to construct a 85 000-membered dihydrobenzopyran library.


Library construction Split synthesis Split-and-pool Dihydrobenzopyran library 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gordon, E.M., Barrett, R.W., Dower, W.J., Fodor, S.P.A and Gallop, M.,Applications of combinatorial technologies to drug discovery. 2. Combinatorial organic synthesis, library screening strategies, and future directions, J. Med. Chem., 37 (1994) 1385–1401.Google Scholar
  2. 2.
    Geysen, M.H., Meloen, R.H. and Barteling, S.J.,Use of peptide synthesis to probe viral antigens for epitopes to a resolution of a single amino acid, Proc. Natl. Acad. Sci. USA, 81 (1984) 3998–4002.Google Scholar
  3. 3.
    Houghten, R.A.,General method for the rapid solid-phase synthesis of large numbers of peptides: Specificity of antigen-antibody interaction at the level of individual amino acids, Proc. Natl. Acad. Sci. USA, 82 (1985) 5131–5135.Google Scholar
  4. 4.
    DeWitt, S.H., Kiely, J.S., Stankovic, C.J., Schroeder, M.C., Reynolds-Cody, D.M. and Pavia, M.R.,‘Diversomers’: An approach to nonpeptide, nonoligomeric chemical diversity, Proc. Natl. Acad. Sci. USA, 90 (1993) 6909–6913.Google Scholar
  5. 5.
    Schnorrenberg, G. and Gerhardt, H.,Fully automatic simultaneous multiple peptide synthesis in micromolar scaleRapid synthesis of series of peptides for screening in biological assays, Tetrahedron, 45 (1989) 7759–7764.Google Scholar
  6. 6.
    Gausepohl, H., Bovlin, C., Kraft, M. and Frank, R.W.,Automated multiple peptide synthesis, Pept. Res., 5 (1992) 315–320.Google Scholar
  7. 7.
    Zuckermann, R.N. and Banville, S.C.,Automated peptide-resin deprotection — Cleavage by a robotic workstation, Pept. Res., 5 (1992) 169–174.Google Scholar
  8. 8.
    Read, J.L., Pirrung, M.C., Stryer, L., Lu, L.A.T. and Solas, D.,Light-directed, spatially addressable parallel chemical synthesis, Science, 251 (1991) 767–773.Google Scholar
  9. 9.
    Furka, A., Sebestyen, F., Asgedom, M. and Dibo, G.,General method for rapid synthesis of mullicomponent peptide mixtures, Int. J. Pept. Protein Res., 37 (1991) 487–493.Google Scholar
  10. 10.
    Lam, K.S., Salmon, S.E., Hersh, E.M., Hruby, V.J., Kazmierski, W.M. and Knapp, R.J.,A new type of synthetic peptide library for identifying ligand-binding activity, Nature, 354 (1991) 82–86.Google Scholar
  11. 11.
    Houghten, R.A., Pinilla, C., Blondell, S.E., Appel, J.R., Dooley, C.T. and Cuervo, J.H.,Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery, Nature, 354 (1991) 84–86.Google Scholar
  12. 12.
    Burgess, K., Lien, A.I. and Wang, N.,Combinatorial technologies involving reiterative division/coupling/recombination: Statistical considerations, J. Med. Chem., 37 (1994) 2985–2987.Google Scholar
  13. 13.
    Brummel, C.L., Lee, I.N.W., Zhou, Y. and Benkovic, S.J.,A mass spectrometric solution to the address problem of combinatorial libraries, Science, 264 (1994) 399–402.Google Scholar
  14. 14.
    Metzger, J.W., Kempter, C., Wiesmuller, K.N. and Jung, G.,Electrospray mass spectrometry and tandem mass spectrometry of synthetic multicomponent peptide mixtures: Determination of composition and purity, Anal. Biochem., 219 (1994) 261–277.Google Scholar
  15. 15.
    Egner, B.J., Langley, G.J. and Bradley, M.,Solid-phase chemistry: Direct monitoring by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. A tool for combinatorial chemistry, J. Org. Chem., 60 (1995) 2652–2653.Google Scholar
  16. 16.
    Brenner, S. and Lerner, R.A.,Encoded combinatorial chemistry, Proc. Natl. Acad. Sci. USA, 89 (1992) 5381–5383.Google Scholar
  17. 17.
    Nielsen, J., Brenner, S. and Janda, K.D.,Synthetic methods for the implementation of encoded combinatorial chemistry, J. Am. Chem. Soc., 115 (1993) 9812–9813.Google Scholar
  18. 18.
    Needels, M.N., Jones, D.G., Tate, E.N., Heinkel, G.L., Koehersperger, L.M., Dower, W.J., Barrett, R.W. and Gallop, M.A.,Generation and screening of an oligonucleotide-encoded synthetic peptide library, Proc. Natl. Acad. Sci. USA, 90 (1993) 10700–10704.Google Scholar
  19. 19.
    Kerr, J.M., Banville, S.C. and Zuckermann, R.N.,Encoded combinatorial peptide libraries containing nonnatural amino acids, J. Am. Chem. Soc., 115 (1993) 2529–2531.Google Scholar
  20. 20.
    Nikolaiev, V., Stierandova, A., Krchñák, V., Seligmann, B., Lam, K.E., Salmon, S.E. and Lebl, M.,Peptide-encoding for structure determination of nonsequenceable polymers within libraries synthesized and tested on solid-phase supports, Pept. Res., 6 (1993) 161–170.Google Scholar
  21. 21.
    Lebl, M., Krchñák, V., Sepetov, N.F., Seligmann, B., Strop, P., Felder, S. and Lam, K.S.,One-bead-one-structure combinatorial libraries, Biopolymers (Pept. Sci.), 37 (1995) 177–198.Google Scholar
  22. 22.
    Ohlmeyer, M.H.J., Swanson, R.N., Dillard, L.W., Reader, J.C., Asouline, G., Kobayashi, R., Wigler, M. and Still, W.C.,Complex synthetic chemical libraries indexed with molecular tags, Proc. Natl. Acad. Sci. USA, 90 (1993) 10922–10926.Google Scholar
  23. 23.
    Nestler, H.P., Bartlett, P.A. and Still, W.C.,A general method for molecular tagging of encoded combinatorial chemistry libraries, J. Org. Chem., 59 (1994) 4723–4724.Google Scholar
  24. 24.
    Hill, H.H. and McMinn, D.G. (Eds.) Detectors for Capillary Chromatography, Chemical Analysis, Vol. 121, Wiley, New York, NY, U.S.A., 1992, pp. 83–107.Google Scholar
  25. 25.
    Baldwin, J.J., Burbaum, J.J., Henderson, I. and Ohlmeyer, M.H.J.,Synthesis of a small-molecule combinatorial library encoded with molecular tags, J. Am. Chem. Soc., 117 (1995) 5588–5589.Google Scholar
  26. 26.
    Burbaum, J.J., Ohlmeyer, M.H.J., Reader, J.C., Henderson, I., Dillard, L.W., Li, G., Randle, T.L., Sigal, N.N., Chelsky, D. and Baldwin, J.J.,A paradigm for drug discovery employing encoded combinatorial libraries, Proc. Natl. Acad. Sci. USA, 92 (1995) 6027–6031.Google Scholar

Copyright information

© ESCOM Science Publishers B.V. 1996

Authors and Affiliations

  • John J. Baldwin
    • 1
  1. 1.Pharmacopeia Inc.PrincetonUSA

Personalised recommendations