Skip to main content
SpringerLink
Log in

A unique geometry of the active site of angiotensin-converting enzyme consistent with structure-activity studies

  • Research Papers
  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Summary

Previous structure-activity studies of captopril and related active angiotensin-converting enzyme (ACE) inhibitors have led to the conclusion that the basic structural requirements for inhibition of ACE involve (a) a terminal carboxyl group; (b) an amido carbonyl group; and (c) different types of effective zinc (Zn) ligand functional groups. Such structural requirements common to a set of compounds acting at the same receptor have been used to define a pharmacophoric pattern of atoms or groups of atoms mutually oriented in space that is necessary for ACE inhibition from a stereochemical point of view. A unique pharmacophore model (within the resolution of approximately 0.15 Å) was observed using a method for systematic search of the conformational hyperspace available to the 28 structurally different molecules under study. The method does not assume a common molecular framework, and, therefore, allows comparison of different compounds that is independent of their absolute orientation.

Consequently, by placing the carboxyl binding group, the binding site for amido carbonyl, and the Zn atom site in positions determined by ideal binding geometry with the inhibitors' functional groups, it was possible to clearly specify a geometry for the active site of ACE.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Marshall, G.R., Barry, C.D., Bosshard, H.E., Dammkochler, R.A. and Dunn, D.A., In Olson, E.C. and Christoffersen, R.E. (Eds) Computer-assisted Drug Design, Washington, DC, ACS Symposium 112, 1979, pp. 205–226.

  2. Marshall, G.R. and Motoc, I., In Burgen, A.S.V., Roberts, G.C.K. and Tute, M.S. (Eds) Molecular Graphics and Drug Design, Elsevier, Amsterdam, 1986, pp. 115–156.

    Google Scholar 

  3. Hartsuck, J.A. and Lipscomb, W.N., In Boyer, P.D. (Ed) The Enzymes, Academic Press, New York, 1971, Vol 3 pp. 1–56.

    Google Scholar 

  4. Schmid, M.E. and Herriott, J.R., J. Mol. Biol. 103 (1976) pp. 175–190.

    PubMed  Google Scholar 

  5. Matthews, B.W., Weaver, L.H. and Kestov, W.R., J. Biol. Chem., 249 (1974) 8030–8044.

    PubMed  Google Scholar 

  6. Cushman, D.W. and Cheung, H.S., Biochem. Pharmacol., 20 (1971) 1637–1648.

    Google Scholar 

  7. Cushman, D.W. and Ondetti, M.A., Prog. Med. Chem., 17 (1980) 41–104.

    PubMed  Google Scholar 

  8. Ondetti, M.A., Williams, N.J., Sabo, E.F., Pluscec, J., Weaver, E.R. and Kocy, O., Biochemistry, 10 (1971) 4033–4039.

    PubMed  Google Scholar 

  9. Cushman, D.W., Cheung, H.S., Sabo, E.F. and Ondetti, M.A., Biochemistry, 16 (1977) 5484–5491.

    PubMed  Google Scholar 

  10. Ondetti, M.A., Rubin, B. and Cushman, D.W., Science, 196 (1977) 441–444.

    PubMed  Google Scholar 

  11. Suh, J.T., Skiles, J.W., Williams, B.E. and Schwab, A., U.S. Patents 4, 256, 761 and 4, 304, 771, 1981.

  12. Hassall, C.H., Krohn, A., Moody, C.J. and Thomas, W.A., FEBS Lett., 147 (1982) 175–179.

    PubMed  Google Scholar 

  13. Bravo, E.L. and Tarazi, R.C., Hypertension, 1 (1979) 39–46.

    PubMed  Google Scholar 

  14. Ondetti, M.A. and Cushman, D.W., Crit. Rev. Biochem., 16 (1984) 381–411.

    Google Scholar 

  15. McEvoy, F.J., Lai, F.M. and Albright, J.D., J. Med. Chem., 26 (1983) 381–393.

    PubMed  Google Scholar 

  16. Thorsett, E.D., Harris, E.E., Aster S., Peterson, E.R., Taub, D. and Patchett, A.A., Biochem. Biophys. Res. Commun., 111 (1983) 166–171.

    PubMed  Google Scholar 

  17. Krohn, A., In Emmet, J.C. (Ed) Second SCI-RSC Medicinal Chem. Symp., 1984, pp. 109–123.

  18. Hassall, C.H., Krohn, A., Moody, C.J. and Thomas, W.A., J. Chem. Soc. Perkin Trans., 1 (1984) 155–164.

    Google Scholar 

  19. Galardy, R.E., Biochemistry, 21 (1982) 5777–5781.

    PubMed  Google Scholar 

  20. Ciabatti, R., Padova, G., Bellasio, E., Tarzia, G., Depaoli, A., Battaglia, F., Cellentani, M., Barone, D. and Baldoli, E., J. Med. Chem., 29 (1986) 411–417.

    PubMed  Google Scholar 

  21. Kim, D.H., Guinosso, C.J., Buzby, G.C. Jr., Herbst, D.R., McCaully, R.J., Wicks, T.C. and Wendt, R.L., J. Med. Chem., 26 (1983) 394–403.

    PubMed  Google Scholar 

  22. Wyvratt, M.J., Tischler, M.H., Ikeler, T.J., Springer, J.P., Tristram, E.W. and Patchett, A.A., In Hruby, V.J. and Rich, D.H. (Eds) Peptides: Structure and Function. Proc. 8th Am. Peptide Symp., Pierce Chemical Company, Rockford, Illinois, 1983, pp 551–554.

  23. Greenlee, W.J., Allibone, P.L., Perlow, D.S., Patchett, A.A., Ulm, E.H. and Vassil, T.C., J. Med. Chem., 28 (1985) 434–442.

    PubMed  Google Scholar 

  24. Galardy, R.E., Kontoyiannidou-Ostrem, V. and Kortylewicz, Z.P., Biochemistry, 22 (1983) 1990–1995.

    PubMed  Google Scholar 

  25. Gruenfeld, N., Stanton, J.L., Yuan, A.M., Ebetino, F.H., Browne, L.J., Gude, C and Huebner, C.F., J. Med. Chem., 26 (1983) 1277–1282.

    PubMed  Google Scholar 

  26. Skiles, J.W., Suh, J.T., Williams, B.E., Menard, P.R., Barton, J.N., Jones, H., Neiss, E.S., Schwab, A., Mann, W.S., Khandwala, A., Wolf, P.S., and Weinryb, I., J. Med. Chem., 29, (1986) 784–796.

    PubMed  Google Scholar 

  27. Petrillo, E.W., Jr. and Ondetti, M.A., Med. Res. Rev., 2 (1982) 1–41.

    PubMed  Google Scholar 

  28. Andrews, P.R., Carson, J.M., Caselli, A., Spark, M.J. and Woods, R., J. Med. Chem., 28 (1985) 393–399.

    PubMed  Google Scholar 

  29. Thorsett, E.D., Harris, E.E., Aster, S.D., Peterson, E.R., Snyder, J.P., Springer, J.P., Hirshfield, J., Tristram, E.W., Patchett, A.A., Ulm, E.H. and Vassil, T.C., J. Med. Chem., 29 (1986) 251–260.

    PubMed  Google Scholar 

  30. Galardy, R.E. and Grobelny, D., J. Med. Chem., 28 (1985) 1422–1427.

    PubMed  Google Scholar 

  31. Wyvratt, M.J. and Patchett, A.A., Med. Res. Rev., 5 (1985) 483–531.

    PubMed  Google Scholar 

  32. Patchett, A.A., Harris, E., Tristram, E.W., Wyvratt, M.J., Wu, M.T., Taub, D., Peterson, E.R., Ikeler, T.J., ten Broeke, J., Payne, L.G., Ondeyka, D.L., Thorsett, E.D., Greenlee, W.J., Lohr, N.S., Hoffsommer, R.D., Joshua, H., Ruyle, W.V., Rothrock, J.W., Aster, S.D., Maycock, A.L., Robinson, F.M., Hirschmann, R., Sweet, C.S., Ulm, E.H., Gross, D.M., Vassil, T.C. and Stone C.A., Nature, 288 (1980) 280–283.

    PubMed  Google Scholar 

  33. Kennard, O. and Watson, D.G., (Eds) Molecular Structures and Dimensions, Vol. 3, Bibliography 1969–1971, Organic and Organometallic Crystal Structures, N.V.A. Oosthoek's Uitgevers Mij. Utrecht, 1971.

  34. SYBYL. Molecular modeling system. Tripos Associates, St. Louis, Missouri.

  35. Klyne, W. and Prelog, V., Experientia, 16 (1960) 521–523.

    Google Scholar 

  36. Motoc, I., Dammkoehler, R.A. and Marshall, G.R., In Trinajstic, N. (Ed) Mathematical and Computational Concepts in Chemistry, Ellis Horwood Ltd., Chichester, 1986, pp. 222–251.

    Google Scholar 

  37. Motoc, I., Dammkoehler, R.A., Mayer, D. and Labanowski, J., Quant. Struct.-Act. Relat., 5 (1986) 99–105.

    Google Scholar 

  38. Labanowski, J., Motoc, I., Naylor, C.B., Mayer, D. and Dammkoehler, R.A., Quant. Struct.-Act. Relat., 5 (1986) 138–152.

    Google Scholar 

  39. Roques, B.P., Lucas-Soroca, E., Chaillet, P., Costentin, J. and Fournie-Zaluski, M.C., Proc. Natl. Acad. Sci. U.S.A., 80 (1983) 3178–3182.

    PubMed  Google Scholar 

  40. Condon, M.E., Petrillo E.W., Jr., Ryono, D.E., Reid, J.A., Neubeck, R., Puar, M., Heikes, J.E., Sabo, E.F., Losee, K.A., Cushman, D.W. and Ondetii, M.A., J. Med. Chem. 25 (1982) 250–258.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Washington University School of Medicine, 63110, St. Louis, MO, U.S.A.

    Dorica Mayer, Christopher B. Naylor & Garland R. Marshall

  2. Department of Computer Science, Washington University, 63110, St. Louis, MO, U.S.A.

    Ioan Motoc

Authors
  1. Dorica Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher B. Naylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ioan Motoc
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Garland R. Marshall
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mayer, D., Naylor, C.B., Motoc, I. et al. A unique geometry of the active site of angiotensin-converting enzyme consistent with structure-activity studies. J Computer-Aided Mol Des 1, 3–16 (1987). https://doi.org/10.1007/BF01680553

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01680553

Key words

Search

Navigation