Conformational Constraints in the Design of Receptor Selective Peptides: Conformational Analysis and Molecular Dynamics

  • Victor J. Hruby
  • Wieslaw Kazmierski
  • B. Montgomery Pettitt
  • Fahad Al-Obeidi
Part of the Biochemical Endocrinology book series (BIOEND)


Efforts to understand the relationships between the three dimensional structure and topography of a peptide hormone or neuropeptide and its biological activities have been difficult due to the many conformations generally available to these natural products, and the complexity of the hormone-receptor interaction which involves at least three different conformational states in the course of information transfer (Hruby 1981a,b; Hruby and Hadley, 1986; Hruby et al., 1983). A major advance in this area has come with the development of conformational constraints, for example via cyclization (Kessler, 1982; Hruby, 1982, 1985), and their use in the design of more receptor selective, potent, and prolonged acting peptide analogues. A major goal in this area is the design of conformationally constrained analogues with stable conformations and high receptor specificity that can be used as templates to assess the topographical features which are important for ligand-receptor interaction and for transduction to produce a biological response. Strategies for accomplishing these goals are urgently needed. In this paper we will discuss two strategies which we believe can be utilized generally, but at different times, in the course of developing insights into the “biologically active” conformation for a peptide hormone or neurotransmitter.


Molecular Dynamic Simulation Opioid Receptor Peptide Hormone Backbone Conformation Side Chain Group 
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  1. Bates, R.B., Hruby, V.J., and Kriek, G.R., 1981, Methyl-L-Alanyl-O,N-Mmethyl-L-Tyrosyl-L-Alanate, Acta Crystallogr., 35B: 188–191Google Scholar
  2. Brooks, B.R., Broccoleri, R.E., Olafson, B.D., States, D.J., Swaminathan, S. and Karplus, M., 1983, CHARMM: A program for macro-molecular energy, minimization, and dynamics calculations, J. Comput. Chem., 4: 187–217CrossRefGoogle Scholar
  3. Cody, W.L., Hadley, M.E., and Hruby, V.J., 1988a, Cyclic conformationally constrained melanotropin analogues: Structure-function and conformational relationships, in “The Melanotropic Peptides. Vol. III: Mechanism of Action and Biomedical Applications,” M.E. Hadley, ed., CRC Press, Boca Raton, in press, for a reviewGoogle Scholar
  4. Cody, W.L., Stevenson, J.W.S., Al-Obeidi, F., Sugg, E.E., and Hruby, V.J., 1988b, Melanotropin 3-dimensional structural studies by physical methods and computer assisted molecular modeling, In loc. cit., in press, for a reviewGoogle Scholar
  5. Hagler, A.T., 1985, Theoretical simulation of conformation, energetics and dynamics of peptides, in “The Peptide: Analysis, Synthesis, Biology. Vol. 7. Conformation in Biology and Drug Design,” V.J. Hruby, ed., Academic Press, N.Y., pp. 213–299Google Scholar
  6. Hruby, V.J., 1981a, Structure and Conformation related to the activity of peptide hormones, in “Perspectives in Peptide Chemistry”, A. Eberle, R. Geiger and T. Wieland, eds., S. Karger, Basel, pp. 207–220Google Scholar
  7. Hruby, V.J., 1981b, Relation of conformation to biological activity in oxytocin, vasopressin and their analogues, in “Topics in Molecular Pharmacology,” A.S.V. Burgen and G.C.K. Roberts, eds., Elsevier/North Holland, Amsterdam, pp. 99–126Google Scholar
  8. Hruby, V.J., 1982, Conformational restrictions of biologically active peptides via amino acid side chain groups, Life Sciences, 31: 189–199PubMedCrossRefGoogle Scholar
  9. Hruby, V.J., 1985, Design of peptide hormone and neurotransmitter analogues, Trends in Pharmacol. Sci., 6: 259–262CrossRefGoogle Scholar
  10. Hruby, V.J., and Hadley, M.E., 1986, Binding and information transfer in conforraationally restricted peptides, in “Design and Synthesis of Organic Molecules Based on Molecular Recognition,” G. van Binst, ed., Springer-Verlag, Heidelberg, pp. 269–289CrossRefGoogle Scholar
  11. Hruby, V.J., Mosberg, H.I., Sawyer, T.K., Knittel, J.J., Rockway, T.W., Ormberg, J., Darman, P., Chan, W.Y., and Hadley, M.E., 1983, Conformational and dynamic considerations in the design of peptide hormone analogs, Biopolymers, 22: 517–530PubMedCrossRefGoogle Scholar
  12. Hruby, V.J., Wilkes, B.C., Cody, W.L., Sawyer, T.K., and Hadley, M.E., 1984, Melanotropins: Structural, conformational, and biological considerations in the development of superpotent and superprolonged analogs, Peptide Protein Rev., 3: 1–64 for a reviewGoogle Scholar
  13. Hruby, V.J., Wilkes, B.C., Hadley, M.E., Al-Obeidi, F., Sawyer, T.K., Staples, P.J., deVaux, A.E., Dym, O., Castrucci, A.M.L., Hintz, M.F., Riehm, J.R., and Ranga Rao, R., 1987, α-Melanotropin: The minimum active sequence in the frog skin bioassay, J. Med. Chem., 30: 2726–2130CrossRefGoogle Scholar
  14. Kazmierski, W., and Hruby, V.J., 1988, A new approach to receptor ligand design: Synthesis and conformation of a new class of potent and highly selective μ opioid antagonists utilizing tetrahydroisoquinoline carboxylic acid, Tetrahedron, in pressGoogle Scholar
  15. Kazmierski, W., Wire, W.S., Lui, G., Knapp, R., Shook, J.E., Yamamura, H.I., Burks, T.F., and Hruby, V.J., 1988, Design and synthesis of somatostatin analogues with specific topographical properties results in highly potent and specific p opioid receptor antagonists with greatly reduced binding at somatostatin receptors, J. Med. Chem., submittedGoogle Scholar
  16. Kessler, H., 1982, Conformation and biological activity of cyclic peptides, Angew. Chem. Int. Ed., 21: 512–523.CrossRefGoogle Scholar
  17. Lewis, P.N., Momany, F.A., and Scheraga, H.A., 1973, Chain reversals in proteins, Biochim. Biophys. Acta, 303: 211–229PubMedCrossRefGoogle Scholar
  18. Nikiforovich, G.V., Shenderovich, M.D., and Chipens, G.I., 1981, The space structures of α-melanotropin, FEBS Lett., 126: 180–182PubMedCrossRefGoogle Scholar
  19. Pelton, J.T., Gulya, K., Hruby, V.J., Duckies, S., and Yamamura, H.I., 1985a, Somatostatin analogues with affinity for opiate receptors in rat brain binding assay, Peptides, 6: 159–163CrossRefGoogle Scholar
  20. Pelton, J.T., Gulya, K., Hruby, V.J., Duckies, S.P., and Yamamura, H.I., 1985b, Conformationally restricted analogs of somatostatin with high μ-opiate receptor specificity, Proc. Natl. Acad. Sci. U.S.A., 82: 236–239CrossRefGoogle Scholar
  21. Pelton, J.T., Kazmierski, W., Gulya, K., Yamamura, H.I., and Hruby, V.J., 1986, Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for mu opioid receptors, J. Med. Chem. 29: 2370–2375PubMedCrossRefGoogle Scholar
  22. Pelton, J.T., Whalon, M., Cody, W.L., and Hruby, V.J., 1987, Conformation of D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP-NH2) a highly selective mu-opioid antagonist peptide by 1H and 13C NMR, Int. J. Peptide Protein Res., in pressGoogle Scholar
  23. Richardson, J.S., 1981, The anatomy and toxonomy of protein structure, Adv. Protein Chem., 34: 168–339Google Scholar
  24. Sawyer, T.K., 1982, α-Melanotropin: Chemical nature and mechanism of biological action, Ph.D. Dissertation, University of Arizona.Google Scholar
  25. Sawyer, T.K., Sanfilippo, P.J., Hruby, V.J., Engel, M.H., Heward, C.B., Burnett, J.B., and Hadley, M.E., 1980, [Nle4, D-Phe7] α-Melanocyte stimulating hormone: A highly potent α-melanotropin with ultra long biological activity, Proc. Natl. Acad. Sci. U.S.A., 77: 5754–5758PubMedCrossRefGoogle Scholar
  26. Sawyer, T.K., Hruby, V.J., Darman, P.S., and Hadley, M.E., 1982, [4-Half-cystine, 10-Half-Cystine]- α-Melanocyte stimulating hormone: A cyclic α-melanotropin exhibiting superagonist biological activity, Proc. Natl. Acad. Sci. U.S.A., 79: 1751–1755PubMedCrossRefGoogle Scholar
  27. Sawyer, T.K., Hruby, V.J., Hadley, M.E., and Engel, M.H., 1983, α-Melancyte stimulating hormone: Chemical nature and mechanism of action, Amer. Zool., 23: 529–540Google Scholar
  28. Schwyzer, R., 1977, ACTH: A short introductory review, Ann. N.Y. Acad. Sci., 297: 3–25PubMedCrossRefGoogle Scholar
  29. Shook, J.E., Pelton, J.T., Lemcke, P.F., Porreca, F., Hruby, V.J., and Burks, T.F., 1987b, Mu opioid antagonist properties of a cyclic somatostatin octapeptide in vivo: Identification of mu receptor related functions, J. Phrmacol. Exp. Therap., 242: 1–7Google Scholar
  30. Shook, J.E., Pelton, J.T., Wire, W.S., Herning, L.D., Hruby, V.J., and Burks, T.F., 1987a, Pharmacological evaluation of a cyclic somatostatin analog with antagonist activity at mu-opioid receptors in vitro, J. Pharmacol. Exp. Therap., 240: 772–222Google Scholar
  31. Sugg, E.E., Tourwe, D., Kazmierski, W., Hruby, V.J., and Van Binst, G., 1988, Proton NMR investigation of the conformational influence of penicillamine residue on the disulfide ring system of opioid receptor selective somatostatin analogues, Int. J. Peptide Protein Res., in pressGoogle Scholar
  32. Sugg, E.E., Tourwe, D., Kazmierski, W., Van Binst, G., Shook, J.E., Yamamura, H.I., Burks, T.F., and Hruby, V.J., 1987, Syntheses and biological activities of somatostatin analogues related to CTP with changes in the 7 position, Int. J. Peptide Protein Res., submittedGoogle Scholar
  33. Venkataraghavan, B., and Feldmann, R.J., 1985, Macromolecular Structure and Specificity: Computer-assisted modeling and application,” Ann. N.Y. Acad. Sci., 439: 1–209CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Victor J. Hruby
    • 1
  • Wieslaw Kazmierski
    • 1
  • B. Montgomery Pettitt
    • 2
  • Fahad Al-Obeidi
    • 1
  1. 1.Department of ChemistryUniversity of ArizonaTucsonUSA
  2. 2.Department of ChemistryUniversity of HoustonHoustonUSA

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