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Molecular Modeling of Renin Inhibitor P2 Substituents

  • E. A. Lunney
  • C. C. Humblet
  • J. T. Repine
  • T. L. Blundell
  • J. B. Cooper
  • B. L. Sibanda
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 306)

Abstract

In the absence of an accurate three-dimensional structure of human renin, the crystal structures of fungal enzymes have provided reasonable templates for the elaboration of a renin model.1 In addition, the increasing number of bound inhibitor structures determined from co-crystallizations with endothiapepsin,2 have considerably enhanced our understanding of the multiple binding modes available to the side chains. These experimental data have formed the bases for molecular modeling studies3 applied to a limited series of highly flexible thiourea P2 side chains. The results provide evidence for an inter-sidechain dependency that will ultimately govern the particular binding affinity. These findings are in agreement with an independent study recently reported in the literature.4

Keywords

Molecular Modeling Renin Inhibitor Molecular Modeling Studies3 Limited Series Strong Binding Affinity 
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.

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References

  1. 1.
    T. L. Blundell, B. L. Sibanda, A. M. Hemmings, S. I. Foundling, I. J. Tickle, L. H. Pearl and S. P. Wood, A rational approach to the design of renin inhibitors, in: “Molecular Graphics and Drug Design,” Elsevier Science, B.V. (Biomedical Division), Amsterdam (1986).Google Scholar
  2. 2.
    T. L. Blundell, J. Cooper and S. I. Foundling, On the rational design of renin inhibitors: x-ray studies of aspartic proteinases complexed with transition-state analogues, Biochem. 26: 5585 (1987).CrossRefGoogle Scholar
  3. 3.
    The molecular modeling studies were carried out using the Sybyl software package (Version 3.5), Tripos Associates, Inc., a subsidiary of Evans and Sutherland, 1699 S. Hanley Rd., Suite 303, St. Louis, Missouri 63144.Google Scholar
  4. 4.
    D. E. Epps, J. Cheney, H. Schostarez, T. K. Sawyer, M. Prairie, W. C. Krueger and F. Mandel, Thermodynamics of the interaction of inhibitors with the binding site of recombinant human renin, J. Med. Chem. 33: 2080 (1990).PubMedCrossRefGoogle Scholar
  5. 5.
    (a) F. H. Allen, O. Kennard and R. Taylor, Systematic analysis of structural data as a research technique in organic chemistry, Acc. Chem. Res. 16: 146 (1983). (b) F. H. Allen, S. Bellard, M. D. Brice, B. A. Cartwright, A. Doubleday, H. Higgs, T. Hummelink, B. G. Hummelink-Peters, O. Kennard, W. D. S. Motherwell, J. R. Rodgers and D. G. Watson, Acta. Crystallogr. B35:2331 (1979).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • E. A. Lunney
    • 1
  • C. C. Humblet
    • 1
  • J. T. Repine
    • 1
  • T. L. Blundell
    • 2
  • J. B. Cooper
    • 2
  • B. L. Sibanda
    • 2
  1. 1.Parke-Davis Pharmaceutical ResearchAnn ArborUSA
  2. 2.Laboratory of Molecular Biology, Department of CrystallographyBirkbeck CollegeLondonUK

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