Advertisement

The Role of Energy Calculations in the Design, Synthesis and Study of Biologically Active Iron (III) Carriers

  • S. Lifson
  • C. E. Felder
  • J. Libman
  • A. Shanzer
Chapter
Part of the NATO ASI Series book series (ASIC, volume 426)

Abstract

The paper highlights the contribution of energy calculations in the design, synthesis and examination of iron(III) (ferric ion) binding molecules whose biological activity is governed by (i) their capability to bind iron(III) and (ii) the fit of their iron(III) complexes to specific membrane receptors. It describes the concepts that guide the principal design of such iron(III) binders, presents a cyclic, experimental-computational algorithm for the detailed design of these compounds, and elucidates the in vitro and in vivo performance of the synthesized compounds by joining experimental and theoretical methods in a mutually supporting interactive approach.

Our conceptual design is governed by assembling families of ion binding molecules by combinational coupling of functional elements and structural elements around symmetric supports. This design provides a series of systematically modified compounds for comparison. The conformations and energies of the members of such a families, in both the free and the complexed states, are then calculated by our empirical force field. These calculations, although of limited accuracy, enable to choose the most promising candidates for synthesis. Once synthesized, the compounds’ physico-chemical and biological properties as iron (III) carriers are examined experimentally. The interactive theoretical-experimental cycle is then closed by applying our computational results for the detailed interpretation of experimental data.

Keywords

Binding Efficiency Vibrational Circular Dichroism Principal Design Microbial Iron Chiral Amino Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. (1).
    Winkelmann, G.; van der Helm, D. and Neilands, J. B. Iron Transport in Microbes, Plants and Animals; VCH Verlagsgesellschaft mbH, D-6940: Weinheim, Germany, 1987.Google Scholar
  2. (2).
    Neilands, J. B. 1984 Structure and Bonding 58, 1–24.CrossRefGoogle Scholar
  3. (3).
    Emery, T. 1978 Metal Ions in Biological Systems 7 77–126.Google Scholar
  4. (4).
    Raymond, K. N. and Carrano, C. J. 1979 Acc. Chem. Res. 12, 183.CrossRefGoogle Scholar
  5. (5).
    Raymond, K. N.; Mueller, G. and Matzanke, B. F. 1984 Top. Cur. Chem. 123. 49–102.CrossRefGoogle Scholar
  6. (6).
    Matzanke, B. F.; Muller-Matzanke, G. and Raymond, K. N. Iron Carriers and Iron Proteins; VCH Publishers: NY, 1989; Vol. 5, pp. 1–121.Google Scholar
  7. (7).
    Hider, R. C. 1984 Structure and Bonding 58, 25–87.CrossRefGoogle Scholar
  8. (8).
    Bagg, A. and Neilands, J. B. 1987 Microbiology Rev. 51, 509.Google Scholar
  9. (9).
    Emery, T.; Emery, L. and Olsen, R. K. 1984 Biochem. Biophys. Res. Commun. 119, 1191.Google Scholar
  10. (10).
    Winkelmann, G. 1979 FEBS Letters 97, 43–46.CrossRefGoogle Scholar
  11. (11).
    Winkelmann, G. and Braun, V. 1981 FEMS Microbiol Letters 11, 237–241.CrossRefGoogle Scholar
  12. (12).
    Neilands, J. B.; Erickson, T. J. and Rastetter, W. H. 1981 J. Biol. Chem. 256, 3831.Google Scholar
  13. (13).
    Lifson, S.; Felder, C. E.; Shanzer, A. and Libman, J. In Synthesis of Macrocycles: The Design of Selective Complexing Agents; Izatt, R. M. and Christensen, J. J., Ed.; John Wiley and Sons: N. Y., 1987; Vol. 3; pp. 241–307.Google Scholar
  14. (14).
    Burkert, V. and Allinger, N. L. Molecular Mechanics; ACS Monograph: 1982; Vol. 177.Google Scholar
  15. (16).
    Lifson, S. and Warshel, A. 1968 J. Chem. Phys. 49 5116.CrossRefGoogle Scholar
  16. (17).
    Warshel, A. and Lifson, S. 1970 J. Chem. Phys. 53, 582.CrossRefGoogle Scholar
  17. (18).
    Lifson, S. and Stern, P. 1982 J. Chem. Phys. 77, 4542.CrossRefGoogle Scholar
  18. (19).
    Hagler, A. T. and Lifson, S. 1974 J. Am. Chem. Soc. 96, 5319.CrossRefGoogle Scholar
  19. (20).
    Lifson, S.; Hagler, A. T. and Dauber, P. 1979 J. Am. Chem. Soc. 101. 5111–5121.CrossRefGoogle Scholar
  20. (21).
    Hagler, A. T.; Stern, P. S.; Sharon, R.; Becker, J. M. and Naider, F. 1979 J. Am. Chem. Soc. 101, 6842.CrossRefGoogle Scholar
  21. (22).
    Lifson, S.; Felder, C. E. and Shanzer, A. 1983 J. Am. Chem. Soc. 105. 3866–3875.CrossRefGoogle Scholar
  22. (23).
    Allen, F. H.; Bellard, S.; Brice, M. D.; Cartwright, B. A.; Doubleday, A.; Higgs, H.; Hummelink, T.; Hummelink-Peters, B. G.; Kennard, O.; Motherwell, W. D. S.; Rodgers, J. R. and Watson, D. G. 1979 Acta. Crystallogr. B35, 2331.Google Scholar
  23. (24).
    Lifson, S.; Felder, C. E. and Shanzer, A. 1984 Biochemistry 23, 2577–2590.CrossRefGoogle Scholar
  24. (25).
    Lifson, S.; Felder, C. E. and Shanzer, A. 1984 Journal of Biomolecular Structure and Dynamics 2, 641–661.CrossRefGoogle Scholar
  25. (26).
    Lifson, S. and Felder, C. E. 1987 Acta Cryst. B43, 179–187.CrossRefGoogle Scholar
  26. (27).
    Shanzer, A. and Libman, J. In CRC-Handbook of Microbial Iron Chelates; Winkelmann, G., Ed.; CRC Press, Inc.: 1991; pp. 309.Google Scholar
  27. (28).
    Tor, Y.; Libman, J.; Shanzer, A.; Felder, C. E. and Lifson, S. 1992 J. Am. Chem. Soc. 114, 6661–6671.CrossRefGoogle Scholar
  28. (29).
    Yakirevitch, P.; Rochel. N.; Albrecht-Gary, A.-M.; Libman, J. and Shanzer, A. 1993 Inorg. Chem. 32, 1779–1787.CrossRefGoogle Scholar
  29. (30).
    Dayan, I.; Libman, J.; Agi, Y. and Shanzer, A. 1993 Inorg. Chem. 32, 1467–1475.CrossRefGoogle Scholar
  30. (31).
    Shanzer, A.; Libman, J.; Yakirevitch, P.; Hadar, Y.; Chen, Y. and Jurkevitch, E. 1993 Chirality 5, 359–365.CrossRefGoogle Scholar
  31. (32).
    Yakirevitch, P.; Hadar, Y.; Chen, Y.; Libman, J. and Shanzer, A. 1994 Microbiology In Press.Google Scholar
  32. (33).
    Shanzer, A.; Libman, J.; Lazar, R.; Tor, Y. and Emery, T. 1988 Biochem. Biophys. Res. Commun. 157. 389–394.CrossRefGoogle Scholar
  33. (34).
    Berner, I.; Yakirevitch, P.; Libman, J.; Shanzer, A. and Winkelmann, G. 1991 Biology of Metals 4, 186–191.CrossRefGoogle Scholar
  34. (35).
    Jurkevitch, E.; Hadar, Y.; Chen, Y.; Libman, J. and Shanzer, A. 1992 J. Bacteriol. 174, 78–83.Google Scholar
  35. (36).
    Shanzer, A.; Libman, J.; Lifson, S. and Felder, C. E. 1986 J. Amer. Chem. Soc. 108 7609–7619.CrossRefGoogle Scholar
  36. (37).
    Burnham, B. F. and Neilands, J. B. 1960 J. Biol. Chem. 236, 554.Google Scholar
  37. (38).
    Emery, T. 1971 Biochemistry 10, 1483–1488.CrossRefGoogle Scholar
  38. (39).
    van der Helm, D.; Baker, J. R.; Eng-Wilmot; D.L., H., M.B. and Loghry, R. A. 1980 J. Amer. Chem. Soc. 102, 4224–4231.CrossRefGoogle Scholar
  39. (40).
    Harris, W. R. and Raymond, K. N. 1979 J. Amer. Chem. Soc. 101, 6534.CrossRefGoogle Scholar
  40. (41).
    Harris, W. R.; Carrano, C. J.; Cooper, S. R.; Sofen, S. R.; Avdeef, A. E.; McArdle, J. V. and Raymond, K. N. 1979 J. Am. Chem. Soc. 101, 6097.CrossRefGoogle Scholar
  41. (42).
    Harris, W. R. and Raymond, K. N. 1979 J. Am. Chem. Soc. 101, 6534.CrossRefGoogle Scholar
  42. (43).
    Harris, W. R.; Raymond, K. N. and Weitl, F. L. 1981 J. Amer. Chem.Soc. 103. 2667.Google Scholar
  43. (44).
    Pecoraro, V. L; Weitl, F. L and Raymond, K. N. 1981 J. Amer. Chem. Soc. 103, 5133.CrossRefGoogle Scholar
  44. (45).
    Tor, Y.; Libman, J.; Shanzer, A. and Lifson, S. 1987 J. Amer. Chem. Soc. 109. 6517.CrossRefGoogle Scholar
  45. (46).
    Shanzer, A.; Libman, J. and Frolow, F. 1981 J. Am. Chem. Soc. 103. 7339.CrossRefGoogle Scholar
  46. (47).
    Shanzer, A. and Libman, J. 1983 J. Chem. Soc., Chem. Comm. 846.Google Scholar
  47. (48).
    Karpishin, T. B. and Raymond, K. N. 1992 Angew. Chem. Int. Ed. Engl. 31 466.CrossRefGoogle Scholar
  48. (49).
    Tor, Y.; Libman, J.; Shanzer, A.; Felder, C. E. and Lifson, S. 1992 J. Am. Chem. Soc. 114, 6653–6661.CrossRefGoogle Scholar
  49. (50).
    Tor, Y.; Libman, J.; Shanzer, A.; Felder, C. E. and Lifson, S. 1987 J. Chem. Soc., Chem. Comm. 749–750.Google Scholar
  50. (51).
    Paterlini, M. G.; Freedman, T. B.; Nafie, L. A.; Tor, Y. and Shanzer, A. 1992 Biopolymers 32, 765–782.CrossRefGoogle Scholar
  51. (52).
    Tor, Y. Ph. D. Thesis, 1990, Weizmann Institute of Science, Rehovot, Israel.Google Scholar
  52. (53).
    Stack, T. D. P.; Hou, Z. and Raymond, K. N. 1993 J. Am. Chem. Soc. 115. 6466–6467.CrossRefGoogle Scholar
  53. (54).
    Tor, Y.; Libman, J. and Shanzer, A. 1987 J. Amer. Chem. Soc. 109. 6518–6519.CrossRefGoogle Scholar
  54. (55).
    Borgias, B. A.; Barclay, S. J. and Raymond, K. N. 1986 J. Coord. Chem. 15, 109.CrossRefGoogle Scholar
  55. (56).
    Leong, J. and Raymond, K. N. 1975 J. Amer. Chem. Soc. 97, 293–296.CrossRefGoogle Scholar
  56. (57).
    Hossain, M. B.; Jalal, M. A. F. and Van der Helm, D. 1986 Acta Cryst. C42. 1305.Google Scholar
  57. (58).
    Muller, N. and Falk, A. 1991, Computer Program Ball & Stick, Ver. 2.3 for Maclntosch, Cherwell Scientific, Oxford, UK.Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1994

Authors and Affiliations

  • S. Lifson
    • 1
  • C. E. Felder
    • 1
  • J. Libman
    • 2
  • A. Shanzer
    • 2
  1. 1.Departments of Chemical PhysicsThe Weizmann Institute of ScienceRehovotIsrael
  2. 2.Departments of Organic ChemistryThe Weizmann Institute of ScienceRehovotIsrael

Personalised recommendations