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Design considerations and computer modeling related to the development of molecular scaffolds and peptide mimetics for combinatorial chemistry

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Summary

A critical issue in drug discovery utilizing combinatorial chemistry as part of the discovery process is the choice of scaffolds to be used for a proper presentation, in a three-dimensional space, of the critical elements of structure necessary for molecular recognition (binding) and information transfer (agonist/ antagonist). In the case of polypeptide ligands, considerations related to the properties of various backbone structures (α-helix, β-sheets, etc.; φ, ψ space) and those related to three-dimensional presentation of side-chain moieties (topography; χ (chi) space) must be addressed, although they often present quite different elements in the molecular recognition puzzle. We have addressed aspects of this problem by examining the three-dimensional structures of chemically different scaffolds at various distances from the scaffold to evaluate their putative diversity. We find that chemically diverse scaffolds can readily become topographically similar. We suggest a topographical approach involving design in chi space to deal with these problems.

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References

  1. Sawyer, T.K.,Peptidomimetic design and chemical approaches to peptide metabolism, In Taylor, M.D. and Amidon, G.L. (Eds.) Peptide-Based Drug Design, American Chemical Society, Washington, DC, U.S.A., 1995, pp. 387–422.

    Google Scholar 

  2. Giannis, A. and Kolter, T.,Peptidomimetics for receptor ligands — discovery, development and medical perspectives, Angew. Chem. Int. Ed. Engl., 32 (1993) 1244–1267.

    Google Scholar 

  3. Hruby, V.J., Al-Obeidi, F. and Kazmierski, W.M.,Emerging approaches in the molecular design of receptor-selective peptide ligands: Conformational, topographical and dynamic considerations, Biochem. J., 268 (1990) 249–262.

    Google Scholar 

  4. Nicolás, E., Russell, K.C. and Hruby, V.J.,Asymmetric 1,4-addition of organocuprates to chiral α,β-unsaturated N-acyl-4-phenyl-2-oxazolidinones: A new approach to the synthesis of chiral β-branched carboxylic acids, J. Org. Chem., 58 (1993) 766–770.

    Google Scholar 

  5. Li, G., Jarosinski, M.A. and Hruby, V.J.,Diastereospecific tandem Michael-like additionlelectrophilic bromination: A one-pot tandem asymmetric synthesis of precursors of unusual amino acids, Tetrahedron Lett., 34 (1993) 2561–2564.

    Google Scholar 

  6. Qian, X., Russell, K.C., Boteju, L.W. and Hruby, V.J.,Stereoselective total synthesis of topographically constrained designer amino acids: 2′,6′-Dimethyl-β-methyltyrosines, Tetrahedron, 51 (1995) 1033–1054.

    Google Scholar 

  7. 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) 82–84.

    Google Scholar 

  8. Lam, K.S., Lebl, M., Wade, S., Stierandova, A., Khattri, P., Collins, N. and Hruby, V.J.,Streptavidin-peptide interaction as a model system for molecular recognition, In Hodges, R.S. and Smith, J.A. (Eds.) Peptides: Chemistry, Structure and Biology (Proceedings of the 13th American Peptide Symposium), ESCOM, Leiden, The Netherlands, 1994, pp. 1005–1006.

    Google Scholar 

  9. Lam, K.S. and Lebl, M.,Streptavidin and Avidin recognize peptide ligands with different motifs, Immunomethods, 1 (1992) 11–15.

    Google Scholar 

  10. Mohamadi, F., Richards, N.G.J., Guida, W.C., Liskamp, R., Lipton, M., Caufield, C., Chang, G., Hendrickson, T. and Still, W.C.,MacroModel — An integrated software system for modeling organic and bioorganic molecules using molecular mechanics, J. Comput. Chem., 11 (1990) 440–467.

    Google Scholar 

  11. MacroModel, Interactive Molecular Modeling System, v. 4.5, Department of Chemistry, Columbia University, New York, NY, U.S.A., 1994.

  12. Lipton, M. and Still, W.C.,The multiple minimum problem in molecular modeling. Tree searching internal coordinate conformational space, J. Comput. Chem., 9 (1988) 343–355.

    Google Scholar 

  13. Allinger, N.L., Yuh, Y.H. and Lii, J.-H.,Molecular Mechanics. The MM3 force field for hydrocarbons 1, J. Am. Chem. Soc., 111 (1989) 8551–8566.

    Google Scholar 

  14. Weiner, S.J., Kollman, P.A., Case, D.A., Chandra Singh, U., Ghio, C., Alagona, G., Profeta, S. and Weiner, P.J.,A new force field for molecular mechanical simulations of nucleic acids and proteins, J. Am. Chem. Soc., 106 (1984) 765–787.

    Google Scholar 

  15. Weiner, S.J., Kollman, P.A., Nguyen, D.T. and Case, D.A.,An all-atom force field for simulations of proteins and nucleic acids, J. Comput. Chem., 7 (1986) 230–252.

    Google Scholar 

  16. Polak, E. and Ribiere, G.,Rev. Franc. Inf. Rech. Oper., 16 (1969) 35; quoted from Ref. 10.

    Google Scholar 

  17. Burkert, U. and Allinger, N.L., Molecular Mechanics, ACS Monograph 177, American Chemical Society, Washington, DC, U.S.A., 1982, pp. 67–72.

    Google Scholar 

  18. Rykaert, J.-P, Ciccotti, G. and Berendsen, H.J.C.,Numerical integration of the Cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes, J. Comput. Phys., 23 (1977) 327–341.

    Google Scholar 

  19. Kabach, W.,A solution for the best rotation to relate two sets of vectors, Acta Crystallogr., A32 (1976) 922–923.

    Google Scholar 

  20. Balaram, P. and Ramaseshan, S. (Eds.) Molecular Conformation and Biological Interactions, Indian Academy of Science, Bangalore, India, 1991.

    Google Scholar 

  21. Hruby, V.J. and Nikiforovich, G.V.,The Ramachandran plot and beyond: Conformational and topographical considerations in the design of peptides and proteins, In Balaram, P. and Ramasheshan, S. (Eds.) Molecular Conformation and Biological Interactions, Indian Academy of Science, Bangalore, India, 1991, pp. 429–445.

    Google Scholar 

  22. Hruby, V.J.,Conformational restrictions of biologically active peptides via amino acid side-chain groups, Life Sci., 31 (1982) 189–199.

    Google Scholar 

  23. Nicolaou, K.C., Solvino, J.M., Raynor, K., Pietranico, S., Reisine, T., Freidinger, R.M. and Hirschmann, R.,Design of synthesis of a peptidomimetic employing β-d-glucose for scaffolding, J. Am. Chem. Soc., 115 (1993) 12550–12586.

    Google Scholar 

  24. Weber, P.C., Ohlendrof, D.H., Wendoloski, J.J. and Salemme, F.R.,Structural origins of high-affinity biotin binding to Streptavidin, Science, 243 (1989) 85–88.

    Google Scholar 

  25. Devlin, J.J., Panganiban, L.C. and Devlin, P.E.,Random peptide libraries: A source of specific protein-binding molecules, Science, 249 (1990) 404–406.

    Google Scholar 

  26. Katz, B.A.,Binding of protein targets of peptidic leads discovered by phage display: Crystal structures of Streptavidinbound linear and cyclic peptide ligands containing the HPQ sequence, Biochemistry, 34 (1995) 5421–5429.

    Google Scholar 

  27. Giebel, L.B., Cass, R.T., Milligan, D.L., Young, D.C., Arze, R. and Johnson, C.R.,Screening of cyclic peptide phage libraries identifies ligands that bind Streptavidin with high affinities, Biochemistry, 34 (1995) 15430–15435.

    Google Scholar 

  28. Weber, P.C., Wendoloski, J.J., Pantoliano, M.W. and Salemme, F.R.,Crystallographic and thermodynamic comparison of natural and synthetic ligands bound to Streptavidin, J. Am. Chem. Soc., 114 (1992) 3197–3200.

    Google Scholar 

  29. Weber, P.C., Pantoliano, M.W., Simons, D.M. and Salemme, F.R.,Structure-based design of synthetic azalienzine ligands for Streptavidin, J. Am. Chem. Soc., 116 (1994) 2717–2727.

    Google Scholar 

  30. Weber, P.C., Pantoliano, M.W. and Thompson, L.D.,Crystal structure and ligand-binding studies of a screened peptide complexed with Streptavidin, Biochemistry, 31 (1992) 9350–9354.

    Google Scholar 

  31. Katz, B.A., Johnson, C.R. and Cass, R.T.,Structure-based design of high-affinity Streptavidin-binding cyclic peptide ligands containing thioether cross-links, J. Am. Chem. Soc., 117 (1995) 8541–8547.

    Google Scholar 

  32. Jones, M.L. and Kurzban, G.P.,Noncooperativity of biotin binding of tetrameric Streptavidin, Biochemistry, 34 (1995) 11750–11756.

    Google Scholar 

  33. Jiao, D., Russell, K.C. and Hruby, V.J.,Locally constrained tyrosine analogues with restricted side-chain dynamics, Tetrahedron, 49 (1993) 3511–3520.

    Google Scholar 

  34. Qian, X., Kövér, K.E., Shenderovich, M.D., Misicka, A., Zalewska, T., Horvath, R., Davis, P., Porreca, F., Yamamura, H.I. and Hruby, V.J.,Newly discovered stereochemical requirements in side-chain conformation of δ-opioid agonists for recognizing opioid δ-receptors, J. Med. Chem., 37 (1994) 1746–1757.

    Google Scholar 

  35. Qian, X., Shenderovich, M.D., Kövér, K.E., Bilsky, E.J., Horváth, R., Davis, P., Yamamura, H.I., Porreca, F. and Hruby, V.J.,Probing the stereochemical requirements for recognizing opioid δ-receptors through topographical design of the message domain of δ-opioid agonists, J. Am. Chem. Soc., 118 (1996) 7280–7290.

    Google Scholar 

  36. Hruby, V.J., Davis, T.P., Polt, R., Bartosz-Bechowski, H., Misicka, A., Lipkowski, A., Sharma, S.D., Li, G., Bonner, G., Meyer, J.-P, Patel, D., Yamamura, H.I., Porreca, F. and O'Brien, D.F.,A systematic investigation of factors that enhance penetration of peptides across the blood-brain harrier, In Kaumaya, P.T.P. and Hodges, R.S. (Eds.) Peptides: Chemistry, Structure and Biology (Proceedings of the 14th American Peptide Symposium), Mayflower Scientific Ltd., Kingswinford, U.K., 1996, pp. 154–156.

    Google Scholar 

  37. Hruby, V.J., Davis, T.P., Polt, R., Porreca, F., O'Brien, D., Yamamura, H.I., Bartosz, H., Szabo, L., Gillespie, T.J., Misicka, A., Lipkowski, A.W., Qian, X., Li, G., Patel, D. and Bonner, G.,Design and synthesis of peptide ligands with unique biochemical and biological profiles at opioid receptors that cross the blood-brain barrier, Analgesia, 1 (1995) 469–472.

    Google Scholar 

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Author notes

  1. Michal Lebl

    Present address: Houghten Pharmaceuticals Inc., 3550 General Atomics Court, 92121, San Diego, CA, USA

Authors and Affiliations

  1. Department of Chemistry, University of Arizona, 85721, Tucson, AZ, USA

    Victor J. Hruby & Mark Shenderovich

  2. Arizona Cancer Center, University of Arizona, 85724, Tucson, AZ, USA

    Kit S. Lam

  3. Selectide Corporation, a subsidiary of Hoechst Marion Roussel, 1580 E. Hanley Boulevard, 85737, Tucson, AZ, USA

    Michal Lebl

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  1. Victor J. Hruby
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  2. Mark Shenderovich
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  3. Kit S. Lam
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  4. Michal Lebl
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Hruby, V.J., Shenderovich, M., Lam, K.S. et al. Design considerations and computer modeling related to the development of molecular scaffolds and peptide mimetics for combinatorial chemistry. Mol Divers 2, 46–56 (1996). https://doi.org/10.1007/BF01718700

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