Skip to main content
SpringerLink
Log in

Determination of receptor-bound drug conformations by QSAR using flexible fitting to derive a molecular similarity index

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

Summary

Results are presented for a QSAR analysis of bisamidines, using a similarity index as descriptor. The method allows for differences in conformation of bisamidines at the receptor site to be taken into consideration. In particular, it has been suggested by others that pentamidine binds in the minor groove of DNA in a so-called isohelical conformation, and our QSAR supports this suggestion. The molecular similarity index for comparison of molecules can be used as a parameter for correlating and hence rationalising the activity as well as suggesting the design of bioactive molecules. The studied compounds had been evaluated for potency against Leishmania mexicana amazonensis, and this potency was used as a dependent variable in a series of QSAR analyses. For the calculation of similarity indexes, each analogue was in turn superimposed on a chosen lead compound in a reference conformation, either extended or isohelical, maximising overlap and hence similarity by flexible fitting.

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. Tidwell, R.R., Jones, S.K., Geratz, J.D., Ohemeng, K.A., Cory, M. and Hall, J.E., J. Med. Chem., 33 (1990) 1252.

    Google Scholar 

  2. Bell, C.A., Hall, J.E., Kyle, D.E., Grogl, M., Ohmeng, K.A., Allen, M.A. and Tidwell, R.R., Antimicrob. Agents Chemother., 34 (1990) 1381.

    Google Scholar 

  3. Bell, C.A., Cory, M., Farilay, T.A., Hall, J.E. and Tidwell, R.R., Antimicrob. Agents Chemother., 35 (1991) 1099 and references cited therein.

    Google Scholar 

  4. Edwards, K.J., Jenkens, T.C. and Neidle, S., Biochemistry, 31 (1992) 7104.

    Google Scholar 

  5. Lowe, P.R., Sansom, C.E., Schwalbe, C.H. and Stevens, M.F.G., J. Chem. Soc., Chem. Commun., (1989) 1164.

  6. Donkor, I.O., Tidwell, R.R. and Jones, S.K., J. Med. Chem., 37 (1994) 4554.

    Google Scholar 

  7. HyperChem, Release 2 for Silicon Graphics, Autodesk, Inc., Sausalito, CA, 1992.

  8. PIMMS v. 1.46, Oxford Molecular Ltd., Oxford, 1994.

  9. Carbo, R., Leyda, L. and Arnam, M., Int. J. Quantum Chem., 17 (1980) 1185.

    Google Scholar 

  10. ASP v. 3.11, Oxford Molecular Ltd., Oxford, 1994.

  11. TSAR v. 2.31, Oxford Molecular Ltd., Oxford, 1994.

  12. Hansch, C. and Leo, A., Substituent Constants for Correlation Analysis in Chemistry and Biology, Wiley, New York, NY, 1979.

    Google Scholar 

  13. Molconn-X, v. 1.0 for Macintosh, Hall Associates Consulting, Eastern Nazarene College, Quincy, MA, 1991.

  14. Ståle, L. and Wold, S., Prog. Med. Chem., 25 (1988) 291.

    Google Scholar 

  15. Kier, L.B. and Hall, L.H., J. Pharm. Sci., 70 (1981) 583.

    Google Scholar 

  16. Hall, L.H. and Kier, L.B., Bull. Environ. Contam. Toxicol., 32 (1984) 354.

    Google Scholar 

  17. Kier, L.B., Quant. Struct.-Act. Relatsh., 4 (1985) 109.

    Google Scholar 

  18. Kier, L.B., Quant. Struct.-Act. Relatsh., 5 (1986 1, 7.

    Google Scholar 

  19. Kier, L.B., Quant. Struct.-Act. Relatsh., 6 (1987) 8.

    Google Scholar 

  20. Hall, L.H. and Kier, L.B., Quant. Struct.-Act. Relatsh., 9 (1990) 115.

    Google Scholar 

  21. Kier, L.B., Hall, L.H. and Frazer, J.W., J. Math. Chem., 7 (1991) 229.

    Google Scholar 

  22. Hall, L.H., Mohney, B. and Kier, L.B., Quant. Struct.-Act. Relatsh., 10 (1991) 43.

    Google Scholar 

  23. Good, A.C., J. Mol. Graphics, 10 (1992) 144.

    Google Scholar 

  24. Good, A.C., Hodgkin, E.E. and Richards, W.G., J. Chem. Inf. Comput. Sci., 32 (1992) 188.

    Google Scholar 

  25. Good, A.C. and Richards, W.G., J. Chem. Inf. Comput. Sci., 33 (1993) 112.

    Google Scholar 

  26. So, S.S. and Richards, W.G., J. Med. Chem., 35 (1992) 3201.

    Google Scholar 

  27. Good, A.C., So, S.S. and Richards, W.G., J. Med. Chem., 36 (1993) 433.

    Google Scholar 

  28. Good, A.C., Hodgkin, E.E. and Richards, W.G., J. Comput.-Aided Mol. Design, 6 (1992) 513.

    Google Scholar 

  29. Good, A.C. and Richards, W.G., J. Chem. Inf. Comput. Sci., 33 (1993) 112.

    Google Scholar 

  30. Benigni, R., Cottaramusino, M., Giorgi, F. and Gallo, G., J. Med. Chem., 38 (1995) 629.

    Google Scholar 

  31. Martin, Y.C., Quantitative Drug Design: A Critical Introduction, Marcel Dekker, New York, NY, 1978.

    Google Scholar 

  32. Tute, M.S., Adv. Drug Res., 6 (1971) 1.

    Google Scholar 

  33. Tute, M.S., In Hansch, C. (Ed.) Comprehensive Medicinal Chemistry, Vol. 4, Quantitative Drug Design, Pergamon Press, New York, NY, 1990, pp. 1–31.

    Google Scholar 

  34. Koshland, Jr., D.E., J. Cell. Comput. Physiol., 54 (1959) 245.

    Google Scholar 

  35. Koshland, Jr., D.E., Adv. Enzymol. 22 (1960) 45.

    Google Scholar 

  36. Koshland, Jr., D.E., Proc. Natl. Acad. Sci. USA, 44 (1958) 98.

    Google Scholar 

  37. Koshland, Jr., D.E., Adv. Enzyme Regul., 6 (1968) 291.

    Google Scholar 

  38. Koshland, Jr., D.E. and Kirtlwy, M.E., Natl. Cancer Inst. Monogr., 27 (1966) 129.

    Google Scholar 

  39. Lane, A.E., Jenkins, T.C., Brown, T. and Neidle, S., Biochemistry, 30 (1991) 1372.

    Google Scholar 

  40. Sansom, C.E., Laughton, C.A., Neidle, S., Schwalbe, C.H. and Stevens, M.F.G., Anti-Cancer Drug Des., 5 (1990) 143.

    Google Scholar 

  41. Jenkins, T.C., Lane, A.N., Neidle, S. and Brown, D.G., Eur. J. Biochem., 213 (1993) 1175.

    Google Scholar 

  42. Smissman, E.E., Nelson, W.L., LaPidus, J.B. and Day, J.L., J. Med. Chem., 9 (1966) 458.

    Google Scholar 

  43. Armstrong, P.D. and Cannon, J.G., J. Med. Chem., 13 (1970) 1037.

    Google Scholar 

Download references

Author information

Author notes

  1. C. A. Montanari

    Present address: Núcleo de Estudos em Química Medicinal-NEQUIM, Departamento de Química, Universidade Federal de Minas Gerais, Brazil

Authors and Affiliations

  1. Chemical Laboratory, University of Kent, CT2 7NH, Canterbury, Kent, U.K.

    C. A. Montanari, M. S. Tute, A. E. Beezer & J. C. Mitchell

Authors
  1. C. A. Montanari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. S. Tute
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. E. Beezer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. C. Mitchell
    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

Montanari, C.A., Tute, M.S., Beezer, A.E. et al. Determination of receptor-bound drug conformations by QSAR using flexible fitting to derive a molecular similarity index. J Computer-Aided Mol Des 10, 67–73 (1996). https://doi.org/10.1007/BF00124466

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00124466

Keywords

Search

Navigation