Abstract
Peptides represent an extensive class of biologically active molecules. They may be used as leads in the development of novel therapeutic agents provided the pharmacophoric information present within them can be translated into non-peptide analogs that lack the peptide backbone and are stable to proteolysis. This is the rationale for peptidomimetic drug design. Frequently, the β-turn has been implicated as a conformation important for biological recognition of peptides. Empirical evidence from known peptidomimetics, coupled with a theoretical model of peptide binding and the observation that glycine and proline residues are common within the β-turn, has suggested the design of molecules to mimic placement of between two and four of the side-chains. The moderate number of different β-turn conformations, combined with the combinatoric nature of side-chain selection complicates the procedure. In this paper, cluster analysis has been used to classify the arrangement of C_α atoms about the various fragments of the β-turn. Recombination of the observed patterns provides a general model for the β-turn which may be used as an effective screen for potential peptidomimetic scaffolds in chemical databases.
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References
König, W., Peptide and Protein Hormones: Structure, Regulation, Activity, VCH, Weinheim, 1993.
Taylor, M.D. and Amidon, G.L. (Eds) Peptide-Based Drug Design: Controlling Transport and Metabolism, ACS, Washington, DC, 1995.
Stephenson, S.L. and Kenny, A.J., Biochem. J., 241 (1987) 237.
Kahn, M., Synlett., 11 (1993) 821.
Giannis, A. and Kolter, T., Angew. Chem. Int. Ed. Engl., 32 (1993) 1244.
Gante, J., Angew. Chem. Int. Ed. Engl., 33 (1994) 1699.
Damewood, J.R., Rev. Comp. Chem., 9 (1996) 1.
Goodman, M. and Ro, S., In Wolf, M.E. (Ed.) Peptidomimetics for drug design, Vol. 1, Burger' Medicinal Chemistry and Drug Discovery, pp. 803–861.
Farmer, P.S. (1980) In Ariëns, E. J., Drug Design, Vol. 10, Academic Press, New York, NY, 1980, pp. 119–143.
Beck-Sickinger, A.G., Wieland, H.A., Wittneben, H., Willim, K.D., Rudolf, K. and Jung, G., Eur. J. Biochem., 225 (1994) 947.
Peeters, T.L., Macielag, M.J., Depoortere, I., Konteatis, Z., Vantrappen, G., Lessor, R. and Florance, J., Regul. Pept., 40 (1992) 226.
Tam, J.P., Liu, W., Zhang, J.-W., Galantino, M., Bertolero, F., Christiani, C., Vaghi, F. and de Castiglione, R., Peptides, 15 (1994) 703.
Wüthrich, K., NMR of Proteins and Nucleic Acids, John Wiley, New York, NY, 1991.
Rose, G.D., Gierasch, L.M. and Smith, J.A., Adv. Protein Chem., 37 (1985) 1.
Dyson, H.J., Cross, K.J., Houghton, R.A., Wilson, I.A., Wright, P.E. and Lerner, R.A., Nature, 318 (1985) 480.
Veber, D.F., Freidinger, R.M., Perlow, D.S., Paleveda, W.J., Holly, F.W., Strachen, R.G., Nutt, R.F., Arison, B.H., Homnick, C., Randall, W.C., Glitzer, M.S., Saperstein, R. and Hirschmann, R., Nature, 292 (1981) 55.
Kopple, K.D., In Rich, D.H. and Gross, E. (Eds) Peptides: Synthesis, Structure, Function, Pierce Chemical Co., Rockford, IL, 1981, pp. 295–298.
Momany, F.A., J. Am. Chem. Soc., 98 (1976) 2990.
Walter, R., Fed. Proc., 36 (1977) 1872.
Fox, J.W., Vavarek, R.J., Tu, A.T. and Stewart, J.M., Peptides, 1 (1982) 193.
Bradbury, A.F., Smythe, D.G. and Snell, C.R., Nature, 260 (1976) 165.
Ball, J.B., Hughes, R.A., Alewood, P.F. and Andrews, P.R., Tetrahedron, 49 (1993) 3467.
Ball, J.B. and Alewood, P.F., J. Mol. Recogn., 3 (1990) 55.
Garland, S.L. and Dean, P.M., J. Comput.-Aided Mol. Design, 13 (1999) 485.
Milner-White, E.J., Trends Pharmacol. Sci., 10 (1989) 70.
Wilmot, C.M. and Thornton, J.M., J. Mol. Biol., 203 (1988) 221.
Wilmot, C.M. and Thornton, J.M., Protein Eng., 3 (1990) 479.
SYBYL 6.4, 1997, Tripos Associates Inc., St. Louis, MO.
McLachlan, A.D., J. Mol. Biol., 128 (1979) 49.
Ward, J.H., J. Am. Stat. Assoc., 58 (1963) 236.
Mojena, R., Comput. J., 20 (1977) 359.
Abola, E.E., Bernstein, F.C., Bryant, S.H., Koetzle, T.F. and Weng, J., In Allen, F.H., Bergerhoff, G. and Sievers, R. (Eds), Crystallographic Databases: Information Content, Software Systems, Scientific Applications, Data Commission of the International Union of Crystallography, Cambridge, 1987, pp. 107–132.
Ripka, W.C., de Lucca, G.V., Bach, A.C., Pottorf, R.S. and Blaney, J.M., Tetrahedron, 49 (1993) 3609.
Weininger, D., J. Chem. Inf. Comput. Sci., 28 (1988) 31.
Weininger, D., Weininger, A. and Weininger, J. L., J. Chem. Inf. Comput. Sci., 29 (1989) 97.
Rusinko, A., Skell, J.M., Balducci, R., McGarity, C.M. and Pearlman, R.S., Concord: a program for the rapid generation of high-quality approximate 3-D molecular structures, Tripos Associates, St. Louis, MO, 1988.
Hirschmann, R., Sprengeler, P.A., Kawasaki, T., Leahy, J.W., Shakespeare, W.C. and Smith, A.B., Tetrahedron, 49 1993) 3665.
Chemical Design Ltd., Chipping Norton, U.K.
Hoyt, M.J. and Bartlett, P.A., J. Am. Chem. Soc., 120 (1998) 4600.
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Garland, S., Dean, P. Design criteria for molecular mimics of fragments of the β-turn. 1. Cα atom analysis. J Comput Aided Mol Des 13, 469–483 (1999). https://doi.org/10.1023/A:1008045403729
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DOI: https://doi.org/10.1023/A:1008045403729