Journal of Computer-Aided Molecular Design

, Volume 5, Issue 6, pp 571–584 | Cite as

Structure-activity relationship of Ca2+ channel blockers: A study using conformational analysis and chemometric methods

  • L. Belvisi
  • S. Brossa
  • A. Salimbeni
  • C. Scolastico
  • R. Todeschini
Research Papers


A structure-activity relationship study has been done on 8 compounds with the activity known as ‘Ca2+ channel blockers’. Conformational analysis was carried out using a molecular mechanics method. The 3D-QSAR approach was used and the most polar functional groups present in all the molecules were considered. Eight interatomic distances are necessary to define the relative spatial disposition of these relevant molecular fragments. The structure-activity relationship between interatomic distances and biological activity was performed using statistic and chemometric methods. In particular, with Principal Component Analysis, it was possible to reduce the number of interatomic distances: only six of the eight distances are sufficient to describe the system in a useful way. A classification method was iteratively used to select the most probable conformations linked to the biological activity and to build a model able to classify conformations according to their biological behaviour. Cluster analysis on the active selected conformations subsequently allowed the identification of two different geometrical patterns for the active compounds. Finally the validity of the model was verified by correctly predicting the activity of other molecules not used in the construction of the model but possessing known activity.

Key words

Calcium channel blockers Conformational analysis Principal Component Analysis Chemometric methods Pharmacophore identification 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Janis, R.A. and Triggle, D.J., Annu. Rev. Pharmacol. Toxicol., 27 (1987) 347.Google Scholar
  2. 2.
    Janis, R.A. and Triggle, D.J., J. Med. Chem., 26 (1983) 775.Google Scholar
  3. 3.
    Schoemaker, H. and Langer, S.Z., Eur. J. Pharmacol., 111 (1985) 273.Google Scholar
  4. 4.
    Kugita, H., Inone, H., Ikezaki, M., Konda, M. and Takeo, S., Chem. Pharm. Bull., 19 (1971) 595.Google Scholar
  5. 5.
    This compound, synthesized by LusoFarmaco (Menarini Group), will soon be reported in a full paper.Google Scholar
  6. 6.
    Mohacsi, E. and O'Brien, J.P., US Patent, 4,640,930 (1987).Google Scholar
  7. 7.
    Iwao, J., Iso, T. and Oya, M., EP Patent, 233, 291 (1987).Google Scholar
  8. 8.
    Burkett, U. and Allinger, N.L., Molecular Mechanics, American Chemical Society, Washington, DC, 1982.Google Scholar
  9. 9.
    Lipton, M. and Still, W.C., J. Comput. Chem., 9 (1988) 343.Google Scholar
  10. 10.
    MacroModel V2.5 and Batchmin V2.1, Department of Chemistry, Columbia University, New York, NY, 1989.Google Scholar
  11. 11.
    Mohamadi, F., Richards, N.G.J., Guida, W.C., Liskamp, R., Lipton, M., Caufield, C., Chang, G., Hendrickson, T. and Still, W.C., J. Comput. Chem., 11 (1990) 440.Google Scholar
  12. 12.
    Allinger, N.L., J. Am. Chem. Soc., 99 (1977) 8127.Google Scholar
  13. 13.
    Kojic-Prodic, B., Ruzic-Toros, Z., Sunjic, V., Decorte, E. and Moimas, F., Helv. Chim. Acta, 67 (1984) 916.Google Scholar
  14. 14.
    Massart, D.L., Vandeginste, B.G.M., Deming, S.N., Michotte, Y. and Kaufman, L., Chemometrics: A Textbook, Elsevier, Amsterdam, 1988.Google Scholar
  15. 15.
    Mardia, K.V., Kent, J.T. and Bibby, J.M., Multivariate Analysis, Academic Press, London, 1988.Google Scholar
  16. 16.
    Gordon, A.D., Classification, Chapman and Hall, London, 1981.Google Scholar
  17. 17.
    Frank, I.E. and Todeschini, R., personal communication.Google Scholar
  18. 18.
    Bratchell, N., Chemometrics Intelligent Lab. Sys., 6 (1989) 105.Google Scholar
  19. 19.
    Massart, D.L. and Kaufman, L., The Interpretation of Analytical Chemical Data by the Use of Cluster Analysis, Wiley, New York, NY, 1983.Google Scholar
  20. 20.
    Mohacsi, E. and O'Brien, J.P., US Patent, 4,652,561 (1987).Google Scholar
  21. 21.
    Floyd, D.M., Moquin, R.V., Atwal, K.S., Ahmed, S.Z., Spergel, S.H., Gougoutas, J.Z. and Malley, M.F., J. Org. Chem., 55 (1990) 5572.Google Scholar
  22. 22.
    Todeschini, R., Cosentino, U., Frank, I.E. and Moro, G., SCAN-Software for Chemometric Analysis, JerIl Inc., Stanford, CA, 1990.Google Scholar

Copyright information

© ESCOM Science Publishers B.V. 1991

Authors and Affiliations

  • L. Belvisi
    • 1
  • S. Brossa
    • 1
  • A. Salimbeni
    • 2
  • C. Scolastico
    • 1
  • R. Todeschini
    • 3
  1. 1.Dipartimento di Chimica Organica e IndustrialeCentro del C.N.R.MilanItaly
  2. 2.Istituto LusoFarmaco d'Italia S.p.a.MilanItaly
  3. 3.Dipartimento di Chimica Fisica e ElettrochimicaMilanItaly

Personalised recommendations