Overview of Combinatorial Chemistry

Stephen L. Crooks1, Leslie J. Charles1

1 3M Pharmaceuticals, St. Paul, Minnesota
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 9.3
DOI:  10.1002/0471141755.ph0903s10
Online Posting Date:  May, 2001
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This unit provides an overview of combinatorial chemistry, including the design and construction of combinatorial libraries for drug discovery. Strategies and resources for library synthesis are summarized, and examples of combinatorial libraries are given. This unit provides an overview of combinatorial chemistry, including the design and construction of combinatorial libraries fo.

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Table of Contents

  • What is Combinatorial Chemistry?
  • Library Design
  • Library Construction
  • Examples of Libraries
  • Trends and Future Directions
  • Figures
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Literature Cited

Literature Cited
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   Atherton, E. and Sheppard, R. 1989. Solid Phase Peptide Synthesis: A Practical Approach. IRL Press. Oxford.
   Bondy, S. 1998. The role of automation in drug discovery. Current Opinion in Drug Discovery and Development. 1:116‐119.
   Booth, R. and Hodges, J. 1997. Polymer supported quenching reagents for parallel purification. J. Am. Chem. Soc. 119:4882‐4886.
   Brady, S.F., Stauffer, K.J., Lumma, W.C., Smith, G.M., Ramjit, H.G., Lewis, S.D., Lucas, B.J., Gardell, S.J., Lyle, E.A., Appleby, S.D., Cook, J.J., Holahan, M.A., Stranieri, M.T., Lynch, J.J. Jr., Lin, J.H., Chen, I.W., Vastag, K., Naylor‐Olsen, A.M., and Vacca, J.P. 1998. Discovery and development of the novel potent orally active thrombin inhibitor N‐(9‐Hydroxy‐9‐fluorenecarboxy)prolyl trans‐4‐aminocyclohexylmethyl amide (L‐372,460): Coapplications of structure‐based design and rapid multiple analogue synthesis on solid support. J. Med. Chem. 41:401‐406.
   Cavella, D. 1998. Web Alert. Curr. Opin. Drug Discovery Dev. 1:1‐2.
   Cohen, G., Deutsch, J., Fineberg, J., and Levine, A. 1997. Covalent attachment of DNA oligonucleotides to glass. Nucleic Acids Res. 25:911‐912.
   Crowley, J. and Rapoport, H. 1976. Solid phase organic synthesis: Novelty or fundamental concept? Accounts Chem. Res. 9:135‐143.
   Czarnik, A.W. and DeWitt, S.H. 1997. A Practical Guide to Combinatorial Chemistry. Oxford University Press, New York.
   Dolle, R.E. and Nelson, K.H. Jr. 1999. Comprehensive survey of combinatorial library synthesis: 1998. J. Comb. Chem. 1:235‐282.
   Englebretsen, D. and Harding, D. 1992. Solid phase peptide synthesis on hydrophilic supports. Part II. Studies using perloza beaded cellulose. Int. J. Pept. Protein Res. 40:487‐496.
   Flynn, D., Crich, J., Devraj, R., Hockerman, S., Parlow, J., South, M., and Woodard, S. 1997. Chemical library purification strategies based on principles of complementary molecular reactivity and molecular recognition. J. Am. Chem. Soc. 119:4874‐4881.
   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. U.S.A. 81:3998‐4002.
   Gordon, E.M. and Kerwin, J.F. Jr. (eds.). 1998. Combinatorial Chemistry and Molecular Diversity in Drug Discovery. John Wiley & Sons, New York.
   Hermkens, P., Ottenheijm, H., and Rees, D. 1996. Solid phase organic reactions: A review of the recent literature. Tetrahedron 52:4527‐4554.
   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.
   Jacobs, J. W. and Ni, Z.‐J. 1998. Encoded Combinatorial Chemistry. In Combinatorial Chemistry and Molecular Diversity in Drug Discovery (E.M. Gordon and J.F. Kerwin Jr.., eds) pp. 271‐290. John Wiley & Sons, New York.
   Kaldor, S., Siegel, M., Fritz, J., Dressman, B., and Hahn, P. 1996. Use of solid supported nucleophiles and electrophiles for the purification of non‐peptide small molecule libraries. Tetrahedron Lett. 37:7193‐7196.
   Keana, J., Shimizu, M., and Jernstedt, K. 1986. Functionalized Silica gel as a support for solid phase organic synthesis. J Org. Chem. 51:1641‐1644.
   Lebl, M. 1999. Parallel personal comments on “classical” papers in combinatorial chemistry. J. Comb. Chem. 1:3‐24.
   Leznoff, C. 1977. The use of insoluble polymer supports in general organic synthesis. Accounts Chem. Res. 11:327‐333.
   Merrifield, R. and Stewart, J. 1965. Automated peptide synthesis. Nature 207:522‐523.
   Ogbu, C.O., Qabar, M.N., Boatman, P.D., Urban, J., Meara, J.P., Ferguson, M.D., Tulinsky, J., Lum, C., Babu, S., Blaskovich, M.A., Nakanishi, H., Ruan, F., Cao, B., Minarik, R., Little, T., Nelson, S., Nguyen, M., Gall, A., and Kahn, M. 1998. Highly efficient and versatile synthesis of libraries of constrained beta‐strand mimetics. Bioorg. Med. Chem. Lett. 8:2321‐2326.
   Shi, S., Xiao, X.‐y., and Czarnik, A.W. 1998. A combinatorial synthesis of tyrphostins via the “directed sorting” method. Biotechnol. Bioeng. 61:7‐12.
Key References
  Dolle and Nelson, 1999. See above.
  An update that categorizes combinatorial libraries by biological targets and type of library synthesis.
Internet Resources
  Web site for a broad range of references on combinatorial chemistry (including patents). Site includes lists of automation suppliers, companies offering products for combinatorial chemistry, and a list of scientists in the field.
  Web site that lists meetings on combinatorial chemistry, including commentaries where available. Also provides links to other combinatorial chemistry resources.
  The Orchid Biosciences, Inc. Web site. Gives detail on the development of miniaturized technology for syntheses performed in chip‐based formats.
  The Harvard Institute of Chemistry and Cell Biology web site. Gives detail on Schreiber and group's preparation of a 2‐million‐plus compound library constructed to probe biological processes.
  The Illumina Inc. Web site. Producers of fiber optics–based assay systems.
  The Luminex Corporation web site. Producers of assays based on sorting of beads with fluorescent tags.
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