Journal of Computer-Aided Molecular Design

, Volume 18, Issue 11, pp 709–718 | Cite as

Quantitative structure-activity relationships of mutagenic activity from quantum topological descriptors: triazenes and halogenated hydroxyfuranones (mutagen-X) derivatives

  • P. L. A. Popelier
  • P. J. Smith
  • U. A. Chaudry
Article
First Online:
Received:
Accepted:

Summary

The mutagenic activity of 23 triazenes and, in a different set, of 24 halogenated hydroxyfuranones (MX derivatives) is quantitatively related to new features of contemporary molecular wave functions. Nowadays affordable computers are powerful enough to rapidly generate geometry-optimised ab initio wave functions at HF/3-21G*, HF/6-31G* and B3LYP/6-311+G(2d,p) level for all molecules. The bonds of a common molecular skeleton are described by their ab initio bond lengths and local properties provided by the theory of quantum chemical topology (QCT). The chemometric analysis involves two types: one to generate a statistically validated quantitative model, and one to isolate the active center. In the former a genetic algorithm (GA) selects bond descriptors in order to optimise the cross-validation error, q2, followed by a full partial least squares (PLS) analysis, which also yields randomisation statistics. In the latter type principal components (PCs) are constructed from the original bond descriptors and their variables important to the projection (VIPs) are plotted in a histogram. This analysis suggests a preferred mechanistic pathway for the initial hydroxylation of the triazenes, an issue that has remained ambiguous so far. In the case of the hydroxyfuranones the proposed method aids the elucidation of a mechanistic ambivalence.

Keywords

ab initio active center mutagens triazenes hydroxyfuranones (MX) QSAR 
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Voet, D., Voet, J.G. 1995Biochemistry2WileyNew York, USAGoogle Scholar
  2. Maron, D., Ames, B.N. 1983Mutat. Res.,113173Google Scholar
  3. O’Brien, S.E., Popelier, P.L.A. 2001J. Chem. Inf. Comp. Sci.,41764Google Scholar
  4. Shusterman, A.J., Debnath, A.K., Hansch, C., Gregory, W.H., Frank, R.F., Greene, A.C., Watkins, S.F. 1989Mol. Pharm.,36939Google Scholar
  5. Tuppurainen, K., Lotjonen, S. 1993Mutat. Res.,287235Google Scholar
  6. Bader, R.F.W. 1990Atoms in Molecules. A Quantum TheoryOxford University PressOxford, UKGoogle Scholar
  7. Bader, R.F.W. 1985Acc. Chem. Res.,189Google Scholar
  8. Bader, R.F.W. 1991Chem. Rev.,91893Google Scholar
  9. Popelier, P.L.A. 2000Atoms in Molecules. An IntroductionPearson EducationLondon, UKGoogle Scholar
  10. Popelier, P.L.A. 1999J. Phys. Chem. A,1032883Google Scholar
  11. O’Brien, S.E., Popelier, P.L.A. 2002J. Chem. Soc. Perkin Trans.2478Google Scholar
  12. Smith, P.J., Popelier, P.L.A. 2004J. Comput.-Aided Mol. Des.,18135Google Scholar
  13. O’Brien, S.E. and Popelier, P.L.A., ECCOMAS, Barcelona, Spain, 2000.Google Scholar
  14. Popelier, P.L.A., Chaudry, U., Smith, P.J. 2002J. Chem. Soc. Perkin Trans.21231Google Scholar
  15. Chaudry, U.A., Popelier, P.L.A. 2003J. Phys. Chem. A,1074578Google Scholar
  16. Chaudry, U.A., Popelier, P.L.A. 2004J. Org. Chem.,69233Google Scholar
  17. Popelier, P.L.A. 1994Chem. Phys. Lett.,228160Google Scholar
  18. Malcolm, N.O.J., Popelier, P.L.A. 2002J. Comp. Chem.,24437Google Scholar
  19. Bader, R.F.W., Slee, T.S., Cremer, D., Kraka, E. 1983J. Am. Chem. Soc.,1055061Google Scholar
  20. Howard, S.T., Lamarche, O. 2003J. Phys. Org. Chem.,16133Google Scholar
  21. Cioslowski, J., Mixon, S.T. 1991J. Am. Chem. Soc.,1134142Google Scholar
  22. Bader, R.F.W., Nguyen-Dang, T.T., Tal, Y. 1981Rep. Prog. Phys.,44893Google Scholar
  23. Cheeseman, J.R., Carroll, M.T., Bader, R.F.W. 1988Chem. Phys. Lett.,143450Google Scholar
  24. Bader, R.F.W., Preston, H.J.T. 1969Int. J. Quant. Chem.,3327Google Scholar
  25. Schaftenaar, G., Noordik, J.H. 2000J. Comput.-Aided Mol. Des.,14123Google Scholar
  26. GAUSSIAN98. Gaussian 98, Revision A.7, Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Zakrzewski, V. G. Montgomery, J. A., Jr., Stratmann, R.E., Burant, J.C., Dapprich, S., Millam, J. M., Daniels, A.D., Kudin, K.N., Strain, M.C., Farkas, O., Tomasi, J., Barone, V., Cossi, M., Cammi, R., Mennucci, B., Pomelli, C., Adamo, C., Clifford, S., Ochterski, J., Petersson, G.A., Ayala, P.Y., Cui, Q., Morokuma, K., Malick, D.K., Rabuck, A.D., Raghavachari, K., Foresman, J.B., Cioslowski, J., Ortiz, J.V., Baboul, A.G., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Gomperts, R., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Gonzalez, C., Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W., Andres, J.L., Gonzalez, C., Head-Gordon, M., Replogle, E.S. and Pople, J.A., Gaussian, Inc., Pittsburgh, PA, USA, 1998.Google Scholar
  27. Dewar, M.J.S., Zoebisch, E.G., Healy, E.F., Stewart, J.J.P. 1985J. Am. Chem. Soc.,1073902Google Scholar
  28. Foresman, J.B., Frisch, A. 1996Exploring Chemistry with Electronic Structure MethodsGaussian Inc.Pittsburgh, PA USAGoogle Scholar
  29. Becke, A.D. 1993J. Chem. Phys.,985648Google Scholar
  30. MORPHY98. a program written by P.L.A. Popelier with a contribution from R.G.A. Bone, UMIST, Manchester, UK (1998). http://morphy.ch.umist.ac.uk/.Google Scholar
  31. Popelier, P.L.A., Chaudry, U.A. and Smith, P.J., J. Chem. Soc., Perkin Trans. II (2002) 1231.Google Scholar
  32. Wold, S., Sjostrom, M. and Eriksson, L., In Schleyer, P., Encycl. of Comp. Chem. Wiley, Chichester, UK, 1998, p. 2006.Google Scholar
  33. Wold, S., Kettaneh, N., Tjessem, K. 1996J. Chemometr.,10463Google Scholar
  34. Holland, J.H. 1992Adaption in Natural and Artificial SystemsMIT PressCambridge, MA, USAGoogle Scholar
  35. UMETRICS. info@umetrics.com: www.umetrics.com, 2002.Google Scholar
  36. Livingstone, D.J. 1995Data Analysis for ChemistsOxford University PressOxford, UKGoogle Scholar
  37. Maw, H.H., Hall, L.H. 2001J. Chem. Inf. Comput. Sci.,411248Google Scholar
  38. Wise, B.M., Gallagher, N.B. 2003Eigenvector ResearchMansonWA, USAGoogle Scholar
  39. Wold, S., In van de Waterbeemd, H. (Ed.) Chemometric Methods in Molecular Design, VCH, Weinheim, 1995, p.195.Google Scholar
  40. O’Brien, S.E., Dept. of Chemistry, UMIST, Manchester, UK, 2000.Google Scholar
  41. SPSS Inc. version 10.0.7 http://www.spss.com, 2000 ,Chicago, IL ,USAGoogle Scholar
  42. Venger, B.H., Hansch, C., Hatheway, G.J., Amrein, Y.U. 1979J. Med. Chem.,22473Google Scholar
  43. Shusterman, A.J., Johnson, A.S., Hansch, C. 1989Int. J. Quant. Chem.,3619Google Scholar
  44. Hansch, C. 1972Drug Metab. Rev.,11Google Scholar
  45. Pires, J.M., Floriano, W.B., Gaudio, A.C. 1997J. Mol. Struct.,389159Google Scholar
  46. Fukui, K., Yonezawa, T., Nagata, C. 1952J. Chem. Phys.,20722Google Scholar
  47. Ho, M., Schmider, H., Edgecombe, K.E., Smith, V.H. 1994J. Int. J. Quant. Chem. Quant. Chem. Symp.,28215Google Scholar
  48. Popelier, P.L.A., In Ford, M., Livingstone, D.J., Dearden, J. and van de Waterbeemd, H. (Eds.), EuroQSAR2002: Designing Drugs and Crop Protectants: Processes, Problems and Solutions. Blackwell, Oxford, UK, 2003, p. 130.Google Scholar
  49. LaLonde, R.T., Cook, G.P., Perakyla, H., Bu, L. 1992Chem. Res. Toxicol.,4540Google Scholar
  50. Tuppurainen, K. 1999Chemosphere,383015Google Scholar
  51. Tupparainen, K., Lotjonen, S., Lattikainen, R., Vartiainen, T., Maran, U., Strandberg, M., Tamm, T. 1991Mutat. Res.,24797Google Scholar
  52. Tupparainen, K., Lotjonen, S., Laatikainen, R., Vartiainen, T. 1992Mutat. Res.,266181Google Scholar
  53. Poso, A., Tuppurainen, K., Gynther, J. 1994J. Mol. Struct.-Theochem.,304255Google Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • P. L. A. Popelier
    • 1
  • P. J. Smith
    • 1
  • U. A. Chaudry
    • 1
  1. 1.School of ChemistryUniversity of ManchesterManchesterUK

Personalised recommendations