Summary
This review serves to highlight the recent examples of combinatoric methodology as applied to the discovery and optimization of enzyme inhibitors. Early research efforts focused on the identification of polypeptides from libraries as inhibitors of proteases. As solution- and solid-phase chemistries gain in sophistication, libraries containing less peptidic structural motifs have been created. A recurring design stratagem relies on the synthesis of libraries incorporating pharmacophores with known affinity for the target enzyme. Screening of these structure-based libraries has led to the discovery of small-molecule inhibitors of both proteolytic and non-proteolytic enzymes alike. Two tables are provided listing the enzyme targeted libraries through 1996. A name, generic structure and size is given for each library citation, accompanied by the enzyme screen and the structure and potency of the most active library member.
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References
Bastos, M., Maeji, N.J. and Abeles, R.H.,Inhibitors of human heart chymase based on a peptide library, Proc. Natl. Acad. Sci. USA, 92 (1995) 6738–6742.
Campbell, D.A., Bermak, J.C., Burkoth, T.S. and Patel, D.V.,A transition state analogue inhibitor combinatorial library, J. Am. Chem. Soc., 117 (1995) 5381–5382.
Carell, T., Wintner, E.A., Sutherland, A.J., Rebek Jr., J., Dunayevskiy, Y.M. and Vouros, P.,New promise in combinatorial chemistry: Synthesis, characterization, and screening of small-molecule libraries in solution, Chem. Biol., 2 (1995) 171–183.
Chen, C.L., Strop, P., Lebl, M. and Lam, K.S.,One bead-one compound combinatorial peptide library: Different types of screening, Combinatorial Chem., 267 (1996) 211–219.
Seligmann, B., Abdul-Latif, F., Al-Obeidi, F., Flegelova, Z., Issakova, O., Kocis, P., Krchňák, V., Lam, K.S., Lebl, M., Ostrem, J., Safar, P., Sepetov, N., Stierandova, A., Strop, P. and Wildgoose, P.,The construction and use of peptide and nonpeptidic combinatorial libraries to discover enzyme inhibitors, Eur. J. Med. Chem., 30 (Suppl.) (1995) 319s-335s.
Coombs, G.S., Hazzard, J. and Corey, D.R.,Kinetic characterization of a peptide inhibitor of trypsin isolated from a synthetic peptide combinatorial library, Bioorg. Med. Chem. Lett., 5 (1995) 611–614.
Dolle, R.E.,Design, synthesis and evaluation of aspartyl protease libraries using a molecular encoding strategy, Abstract, First Japanese Conference on Combinatorial Chemistry and High Throughput Screening, Cambridge Healthtech Institute, Osaka, Japan, November 7–9, 1996.
Eichler, J. and Houghten, R.A.,Identification of substrate-analog trypsin inhibitors through the screening of synthetic peptide combinatorial libraries, Biochemistry, 32 (1993) 11035–11041.
Eichler, J., Lucka, A.W. and Houghten, R.A.,Cyclic peptide template combinatorial libraries: Synthesis and identification of chymotrypsin inhibitors, Pept. Res., 7 (1994) 300–307.
Foley, M.A., Hassman, A.S., Drewry, D.H., Greer, D.G., Wagner, C.D., Feldman, P.L., Berman, J., Bickett, D.M., McGeeham, G.M., Lambert, M.H. and Green, M.,Rapid synthesis of novel dipeptide inhibitors of human collagenase, Bioorg. Med. Chem. Lett., 6 (1996) 1905–1910.
For a preliminary account see: Gong, B., Chen, X., Cheng, M., Li, R., Kenyon, G.L. and Cohen, F.E.,Structure-based design and solid phase synthesis of cysteine protease inhibitors for parasitic diseases, 212th American Chemical Society Meeting, Orlando, FL, U.S.A., 1996, Abstract MEDI-039.
Jiracek, J., Yiotakis, A., Vincent, B., Checler, F. and Dive, V.,Development of the first potent and selective inhibitor of the zinc endopeptidase neurolysin using a systematic approach based on combinatorial chemistry of phosphinic peptides, J. Biol. Chem., 271 (1996) 19606–19611.
Jiracek, J., Yiotakis, A., Vincent, B., Lecoq, A., Nicolaou, A., Checler, F. and Dive, V.,Development of highly potent and selective phosphinic peptide inhibitors of zinc endopeptidase 24-15 using combinatorial chemistry, J. Biol. Chem., 270 (1995) 21701–21706.
Kick, E.K. and Ellman, J.A.,Expedient method for the solid-phase synthesis of aspartic acid protease inhibitors directed toward the generation of libraries, J. Med. Chem., 38 (1995) 1427–1430.
Lloyd, J., Schmidt, J.B., Hunt, J.T., Barrish, J.C., Little, D.K. and Tymiak, A.A.,Solid phase synthesis of phosphinic acid endothelin converting enzyme inhibitors, Bioorg. Med. Chem. Lett., 6 (1996) 1323–1326.
Murphy, M.M., Schullek, J.R., Gordon, E.M. and Gallop, M.A.,Combinatorial organic synthesis of highly functionalized pyrrolidines: Identification of a potent angiotensin converting enzyme inhibitor from a mercaptoacyl proline library, J. Am. Chem. Soc., 117 (1995) 7029–7030.
Owens, R.A., Gesellchen, P.D., Houchins, B.J. and DiMarchi, R.D.,The rapid identification of HIV protease inhibitors through the synthesis and screening of defined peptide mixtures, Biochem. Biophys. Res. Commun., 181 (1991) 402–408.
Wang, G.T., Li, S., Wideburg, N., Krafft, G.A. and Kempf, D.J.,Synthetic chemical diversity: Solid phase synthesis of libraries of C(2) symmetric inhibitors of HIV protease containing diamino diol and diamino alcohol cores, J. Med. Chem., 38 (1995) 2995–3002.
Rockwell, A., Melden, M., Copeland, R.A., Hardman, K., Decicco, C.P. and DeGrado, W.F.,Complementarity of combinatorial chemistry and structure-based ligand design: Application to the discovery of novel inhibitors of matrix metalloproteinases, J. Am. Chem. Soc., 118 (1996) 10337–10338.
Chabala, J.C., Baldwin, J.J., Burbaum, J.J., Chelsky, D., Dillard, L.W., Henderson, I., Li, G., Ohlmeyer, M.H.J., Randle, T.L., Reader, J.C., Rokosz, L. and Sigal, N.H.,Binary encoded small-molecular libraries in drug discovery and optimization, Perspect. Drug Discov. Design, 2 (1994) 305–318.
Baldwin, J.J., Burbaum, J.J., Henderson, I. and Ohlmeyer, M.H.,Synthesis of a small molecule combinatorial library encoded with molecular tags, J. Am. Chem. Soc., 117 (1995) 5588–5589.
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.,A paradigm for drug discovery employing encoded combinatorial libraries, Proc. Natl. Acad. Sci. USA, 92 (1995) 6027–6031.
Gao, J., Cheng, R.C., Sigal, G.B., Bruce, J.E., Schwartz, B.L., Hofstadler, S.A., Anderson, G.A., Smith, R.D. and Whitesides, G.M.,Screening derivatized peptide libraries for tight binding inhibitors to carbonic anhydrase II by electrospray ionization-mass spectrometry, J. Med. Chem., 39 (1996) 1949–1955.
Lingardo, L.W., Davis, P.W., Ecker, D.J., Herbert, N., Acevedo, O., Sprankle, K., Brennan, T., Schwarcz, L., Freier, S.M. and Wyatt, J.R.,Deconvolution of combinatorial libraries for drug discovery: Experimental comparison of pooling strategies, J. Med. Chem., 39 (1996) 2720–2726.
Look, G.C., Schullek, J.R., Holmes, C.P., Chinn, J.P., Gordon, E.M. and Gallop, M.A.,The identification of cyclooxygenase-1 inhibitors from 4-thiazolidinone combinatorial libraries, Bioorg. Med. Chem. Lett., 6 (1996) 707–712.
Lutzke, R.A.P., Eppens, N.A., Weber, P.A., Houghten, R.A. and Plasterk, R.H.A.,Identification of a hexapeptide inhibitor of the human immunodeficiency virus integrase protein by using a combinatorial chemical library, Proc. Natl. Acad. Sci. USA, 92 (1995) 11456–11460.
Moran, E.J., Sarshar, S., Cargill, J.F., Shahbaz, M.M., Lio, A., Mjalli, A.M.M. and Armstrong, R.W.,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 (1995) 10787–10788.
Norman, T.C., Gray, N.S., Koh, J.T. and Schultz, P.G.,A structure-based library approach to kinase inhibitors, J. Am. Chem. Soc., 118 (1996) 7430–7431.
Gordon, E.M., Gallop, M.A. and Patel, D.V.,Strategy and tactics in combinatorial organic synthesis, applications to drug discovery, Acc. Chem. Res., 29 (1996) 144–154.
Green, J.,Solid phase synthesis of lavendustin A and analogues, J. Org. Chem., 60 (1995) 4287–4290.
Meyers, H.V., Dilley, G.J., Durgin, T.L., Powers, T.S., Winssinger, N.A., Zhu, H. and Pavia, M.R.,Multiple simultaneous synthesis of phenolic libraries, Mol. Div., 1 (1995) 13–20.
Walsh, D.A. and Uwaydah, I.M., U.S. Patent 5 061 720, 1991.
MacDonald, A.A., DeWitt, S.H., Hogan, E.M. and Ramage, R.,A solid phase approach to quinolones using the DIVERSOMER ® technology, Tetrahedron Lett., 37 (1996) 4815–4818.
Ellman, J.A.,Design, synthesis, and evaluation of small-molecule libraries, Acc. Chem. Res., 29 (1996) 132–143.
For a general review on combinatorial methods and solid-phase chemistries see: Ellman, J.A.,Synthesis and application of small molecule libraries, Chem. Rev., 96 (1996) 555–600.
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Dolle, R.E. Discovery of enzyme inhibitors through combinatorial chemistry. Mol Divers 2, 223–236 (1997). https://doi.org/10.1007/BF01715638
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DOI: https://doi.org/10.1007/BF01715638