Skip to main content
SpringerLink
Log in

Evaluation of a novel molecular vibration-based descriptor (EVA) for QSAR studies: 2. Model validation using a benchmark steroid dataset

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

Abstract

The EVA molecular descriptor derived from calculated molecular vibrational frequencies is validated for use in QSAR studies. EVA provides a conformationally sensitive but, unlike 3D-QSAR methods such as CoMFA, superposition-free descriptor that has been shown to perform well with a wide range of datasets and biological endpoints. A detailed study is made using a benchmark steroid dataset with a training/test set division of structures. Intensive statistical validation tests are undertaken including various forms of crossvalidation and repeated random permutation testing. Latent variable score plots show that the distribution of structures in reduced dimensional space can be rationalized in terms of activity classes and that EVA is sensitive to structural inconsistencies. Together, the findings indicate that EVA is a statistically robust means of detecting structure-activity correlations with performance entirely comparable to that of analogous CoMFAs. The EVA descriptor is shown to be conformationally sensitive and as such can be considered to be a 3D descriptor but with the advantage over CoMFA that structural superposition is not required. EVA has the property that in certain situations the conformational sensitivity can be altered through the appropriate choice of the EVA σ parameter.

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. Ferguson, A.M., Heritage, T., Pack, S.E., Philips, L., Rogan, J. and Snaith, P.J., J. Comput.-Aided Mol. Design, 11 (1997) 143.

    Google Scholar 

  2. Turner, D.B., Willett, P., Ferguson, A.M. and Heritage, T., J. Comput.-Aided Mol. Design, 11 (1997) 409.

    Google Scholar 

  3. Cramer, R.D., Patterson, D.E. and Bunce, J.D., J. Am. Chem. Soc., 110 (1988) 5959.

    Google Scholar 

  4. Ginn, C.M.R., Turner, D.B., Willett, P., Ferguson, A.M. and Heritage, T.W., J. Chem. Inf. Comput. Sci., 37 (1997) 23.

    Google Scholar 

  5. Wold, S. and Eriksson, L., In van de Waterbeemd, H. (Ed.), Methods and Principles in Medicinal Chemistry, Vol. 2, Chemometric Methods in Molecular Design, VCH, Weinheim, Germany, 1993, pp. 309–318.

    Google Scholar 

  6. Wagener, M., Sadowski, J. and Gasteiger, J., J. Am. Chem. Soc., 117 (1995) 7769.

    Google Scholar 

  7. Klebe, G., Abraham, U. and Mietzner, T., J. Med. Chem., 37 (1994) 4130.

    Google Scholar 

  8. Cho, S.J. and Tropsha, A., J. Med. Chem., 38 (1995) 1060.

    Google Scholar 

  9. Sybyl 6.3, Tripos Associates Inc., St. Louis, MO, U.S.A.

  10. Wold, S., Ruhe, A., Wold, H. and Dunn III, W.J., SIAM J. Sci. Stat. Comput., 5 (1984) 735.

    Google Scholar 

  11. Dunn, J.F., Nisula, B.C. and Rodbard, D.J., Endocrinol. Metab., 53 (1981) 58.

    Google Scholar 

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

    Google Scholar 

  13. Oxford Molecular Ltd., Oxford, U.K.

  14. Jain, A.N., Koile, K. and Chapman, D., J. Med. Chem., 37 (1994) 2315.

    Google Scholar 

  15. Oprea, T.I., Ciubotariu, D., Sulea, T.I. and Simon, Z., Quant. Struct.-Act. Relatsh., 12 (1993) 21.

    Google Scholar 

  16. Hahn, M. and Rogers, D., J. Med. Chem., 38 (1995) 2091.

    Google Scholar 

  17. Silverman, B.D. and Platt, D.E., J. Med. Chem., 39 (1996) 2129.

    Google Scholar 

  18. Kellogg, G.A., Kier, L.B., Gaillard, P. and Hall, H.H., J. Comput.-Aided Mol. Design, 10 (1996) 513.

    Google Scholar 

  19. Anzali, S., Barnickel, G., Krug, M., Sadowski, J., Wagener, M., Gasteiger, J. and Polanski, J., J. Comput.-Aided Mol. Design, 10 (1996) 521.

    Google Scholar 

  20. Bravi, G., Gancia, E., Mascagni, P., Pegna, M., Todeschini, R. and Zaliani, A., J. Comput.-Aided Mol. Design, 11 (1997) 79.

    Google Scholar 

  21. Schnitker, J., Gopalaswamy, R. and Crippen, G.M., J. Comput.-Aided Mol. Design, 11 (1997) 93.

    Google Scholar 

  22. Allen, F.H., Davies, J.E., Galloy, J.J., Johnson, O., Kennard, O., Macrae, C., Mitchell, E.M., Mitchell, G.F., Smith, J.M. and Watson, D.G., J. Chem. Inf. Comput. Sci., 31 (1991) 187.

    Google Scholar 

  23. Austel, V., In van de Waterbeemd, H. (Ed.), Methods and Principles in Medicinal Chemistry, Vol. 2, Chemometric Methods in Molecular Design, VCH, Weinheim, Germany, 1993, pp. 49–62.

    Google Scholar 

  24. Sjöström, M. and Eriksson, L., In van de Waterbeemd, H. (Ed.), Methods and Principles in Medicinal Chemistry, Vol. 2, Chemometric Methods in Molecular Design, VCH, Weinheim, Germany, 1993, pp. 63–90.

    Google Scholar 

  25. MOPAC version 6.0., Quantum Chemistry Program Exchange (QCPE), Indiana University, Bloomington, IN, U.S.A.

  26. Bush, B.L. and Nachbar Jr., R.B., J. Comput.-Aided Mol. Design, 7 (1993) 587.

    Google Scholar 

  27. Sadowski, J. and Gasteiger, J., J. Chem. Inf. Comput. Sci., 34 (1994) 1000.

    Google Scholar 

  28. Wold, S., In van de Waterbeemd, H. (Ed.), Methods and Principles in Medicinal Chemistry, Vol. 2, Chemometric Methods in Molecular Design, VCH, Weinheim, Germany, 1993, pp. 195–218.

    Google Scholar 

  29. Shao, J., J. Am. Stat. Assoc., 88 (1993) 486.

    Google Scholar 

  30. Topliss, J.G. and Edwards, R.P., J. Med. Chem., 22 (1979) 1238.

    Google Scholar 

  31. Wold, S., Johansson, E. and Cocchi, M., In Kubinyi, H. (Ed.), 3D QSAR in Drug Design: Theory Methods and Applications, ESCOM, Leiden, The Netherlands, 1993, pp. 523–550.

    Google Scholar 

  32. Jonathan, P., McCarthy, W.V. and Roberts, A.M.I., J. Chemometrics, 10 (1996) 189.

    Google Scholar 

  33. Mickelson, K.E., Forsthoefel, J. and Westphal, U., Biochemistry, 20 (1981) 6211.

    Google Scholar 

  34. Scott, A.P. and Radom, L., J. Phys. Chem., 100 (1996) 16502.

    Google Scholar 

  35. MM3(94) Manual (Version 1.0), Tripos Associates Inc., St. Louis, MO, U.S.A. This contains numerous references to the MMx series of programs developed by Norman Allinger and co-workers at the University of Georgia.

  36. AMSOL (version 6.1.1), Oxford Molecular Ltd., Oxford, U.K.

  37. SPARTAN (release 4.0 2b), Wavefunction Inc., Irvine, CA, U.S.A.

  38. GAUSSIAN 92/DFT (Revision G.4), Gaussian Inc., Pittsburgh, PA, U.S.A.

  39. Cruciani, G. and Clementi, S., In van de Waterbeemd, H. (Ed.), Methods and Principles in Medicinal Chemistry, Vol. 3, Advanced Computer-Assisted Techniques in Drug Discovery, VCH, Weinheim, Germany, 1995, pp. 61–88.

    Google Scholar 

  40. Lindgren, F., Geladi, P., Rannar, S. and Wold, S., J. Chemometrics, 8 (1994) 349.

    Google Scholar 

  41. Clementi, S. and Wold, S., In van de Waterbeemd, H. (Ed.), Methods and Principles in Medicinal Chemistry, Vol. 2, Chemometric Methods in Molecular Design, VCH, Weinheim, Germany, 1993, pp. 319–338.

    Google Scholar 

  42. Kroemer, R.T. and Hecht, P., J. Comput.-Aided Mol. Design, 9 (1995) 205.

    Google Scholar 

  43. Muresan, S., Sulea, T., Ciubotariu, D., Kurunczi, L. and Simon, Z., Quant. Struct.-Act. Relatsh., 15 (1996) 31.

    Google Scholar 

  44. CONCORD version 2.9.3., TRIPOS Inc., St. Louis, MO, U.S.A.

  45. Waszkowycz, B., Clark, D.E., Frenkel, D., Li, J., Murray, C.W., Robson, B. and Westhead, D.R., J. Med. Chem., 37 (1994) 3994.

    Google Scholar 

  46. Turner, D.B. and Willett, P., J. Comput.-Aided Mol. Design, manuscript submitted.

Download references

Author information

Authors and Affiliations

  1. Krebs Institute for Biomolecular Research and Department of Information Studies, University of Sheffield, Western Bank, Sheffield, S10 2TN, U.K

    David B. Turner & Peter Willett

  2. Tripos Inc., 1699 South Hanley Road, St, Louis, MO, 63144, U.S.A

    Allan M. Ferguson & Trevor W. Heritage

Authors
  1. David B. Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Willett
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Allan M. Ferguson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Trevor W. Heritage
    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

Turner, D.B., Willett, P., Ferguson, A.M. et al. Evaluation of a novel molecular vibration-based descriptor (EVA) for QSAR studies: 2. Model validation using a benchmark steroid dataset. J Comput Aided Mol Des 13, 271–296 (1999). https://doi.org/10.1023/A:1008012732081

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1008012732081

Search

Navigation