Journal of Computer-Aided Molecular Design

, Volume 14, Issue 4, pp 341–353 | Cite as

3D-QSAR methods on the basis of ligand–receptor complexes. Application of COMBINE and GRID/GOLPE methodologies to a series of CYP1A2 ligands

  • Juan José Lozano
  • Manuel Pastor
  • Gabriele Cruciani
  • Katrin Gaedt
  • Nuria B. Centeno
  • Federico Gago
  • Ferran Sanz

Abstract

Many heterocyclic amines (HCA) present in cooked food exert a genotoxic activity when they are metabolised (N-oxidated) by the human cytochrome P450 1A2 (CYP1A2h). In order to rationalize the observed differences in activity of this enzyme on a series of 12 HCA, 3D-QSAR methods were applied on the basis of models of HCA–CYP1A2h complexes. The CYP1A2h enzyme model has been previously reported and was built by homology modeling based on cytochrome P450 BM3. The complexes were automatically generated applying the AUTODOCK software and refined using AMBER. A COMBINE analysis on the complexes identified the most important enzyme–ligand interactions that account for the differences in activity within the series. A GRID/GOLPE analysis was then performed on just the ligands, in the conformations and orientations found in the modeled complexes. The results from both methods were concordant and confirmed the advantages of incorporating structural information from series of ligand–receptor complexes into 3D-QSAR methodologies.

AUTODOCK COMBINE cooked food heterocyclic amines cytochrome P450 1A2 docking simulation GRID/GOLPE 3D-QSAR 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Black, S.D. and Coon, M.J., Adv. Enzymol. Relat. Areas Mol. Biol., 60 (1987) 35.Google Scholar
  2. 2.
    Peterson, J.A. and Graham, S.E., Structure, 6 (1998) 1079.Google Scholar
  3. 3.
    Sugimura T., Mutat. Res., 376 (1997) 211.Google Scholar
  4. 4.
    Segura, J., Roberts, D.J. and TarrÚs, E.J., J. Pharm. Pharmacol., 41 (1989) 129.Google Scholar
  5. 5.
    Fuhr, U., Strobl, G., Manaut, F., Anders, E., Sörgel, F., López de Brinñas, E., Chu, D.T.W., Pernet, A.G., Mahr, G., Sanz, F. and Staib, H., Mol. Pharmacol., 43 (1993) 191.Google Scholar
  6. 6.
    Shimada, T., Iwasaki, M., Martin, M.V. and Guengerich, F.P., Cancer Res., 49 (1989) 3218.Google Scholar
  7. 7.
    Wakabayashi, K., Nagao, M., Esumi, H. and Sugimura, T., Cancer Res. (suppl.), 52 (1992) 2092.Google Scholar
  8. 8.
    Chang, Y.T., Stiffelman, O.B., Vakser, I.A., Loew, G.H., Bridges, A. and Waskell, L., Protein Eng., 10 (1997) 119.Google Scholar
  9. 9.
    Szklarz, G.D. and Halpert, J.R., Life Sci., 61 (1997) 2507.Google Scholar
  10. 10.
    Lozano, J.J., Lopez-de-Brinas, E., Centeno, N.B., Guido, R. and Sanz, F., J. Comput.-Aided Mol. Design, 11 (1997) 395.Google Scholar
  11. 11.
    Poulos, T.L., Finzel, B.C. and Howard, A.J., Biochemistry, 25 (1986) 5314.Google Scholar
  12. 12.
    Ravichandran, K.G., Boddupalli, S.S., Hasemann, C.A., Peterson, J.A. and Deisenhofer, J., Science, 261 (1993) 731.Google Scholar
  13. 13.
    Hasemann, C.A., Ravichandran, K.G., Peterson, J.A. and Deisenhofer, J., J. Mol. Biol., 236 (1994) 1169.Google Scholar
  14. 14.
    Cupp-Vickery, J.R. and Poulos, T.L., Nat. Struct. Biol., 2 (1995) 144.Google Scholar
  15. 15.
    Uno, T., Michell, E., Aida, K., Lambert, M.H., Darden, T.A., Pedersen, L.G. and Negishi, M., Biochemistry, 36 (1997) 3193.Google Scholar
  16. 16.
    Helms, V. and Wade, R.C., J. Am. Chem. Soc., 120 (1998) 2710.Google Scholar
  17. 17.
    Paulsen, M.D. and Ornstein, R.L., Protein Eng., 9 (1996) 567.Google Scholar
  18. 18.
    Kollman, P., Chem. Rev., 93 (1993) 2395.Google Scholar
  19. 19.
    Ortiz, A.R., Pisabarro, M.T., Gago, F. and Wade, R.C., J.Med. Chem., 36 (1995) 2681.Google Scholar
  20. 20.
    Ortiz, A.R., Pastor, M., Palomer, A., Cruciani, G., Gago, F. and Wade, R.C., J. Med. Chem., 40 (1997) 1136.Google Scholar
  21. 21.
    Perez, C., Pastor, M., Ortiz, A.R. and Gago, F., J. Med. Chem., 41 (1998) 836.Google Scholar
  22. 22.
    Wade, R.C., Ortiz, A.R. and Gago, F., In Kubinyi, H., Folkers, G. and Martin, Y.C. (Eds.), 3D QSAR in Drug Design, Vol. 2, Kluwer/Escom, Dordrecht, 1998, p. 19.Google Scholar
  23. 23.
    Goodford, P., J. Chemometr., 10 (1996) 107.Google Scholar
  24. 24.
    Cramer, R.D., Patterson, D.E. and Bunce, J.D., J. Am. Chem. Soc., 110 (1988) 5959.Google Scholar
  25. 25.
    GOLPE 4.0, Multivariate Infometric Analysis, Perugia, Italy, 1998.Google Scholar
  26. 26.
    Cruciani, G. and Watson, K.A., J. Med. Chem., 37 (1994) 2589.Google Scholar
  27. 27.
    Sugimura, T., Mutat. Res., 150 (1985) 33.Google Scholar
  28. 28.
    Eisenbrand, G. and Tang, W., Toxicology, 84 (1993) 1.Google Scholar
  29. 29.
    GRID v. 15, Molecular Discovery Ltd., Oxford, 1997.Google Scholar
  30. 30.
    Wild, D., Feser, W., Michel, S., Lord, H.L. and Josephy, P.D., Carcinogesis, 16 (1995) 643.Google Scholar
  31. 31.
    Shimada, T. and Guengerich, F.P., Cancer Res., 51 (1991) 5284.Google Scholar
  32. 32.
    Morris, G.M., Goodsell, D.S., Huey, R. and Olson, A.J., J. Comput.-Aided Mol. Design, 10 (1996) 293.Google Scholar
  33. 33.
    Raag, R., Li, H., Jones, B.C. and Poulos, T.L., Biochemistry, 32 (1993) 4571.Google Scholar
  34. 34.
    AMBER (UCSF): Assisted Model Building with Energy Refinement, version 4.1, 1995. Department of Pharmaceutical Chemistry, University of California, San Francisco, CA.Google Scholar
  35. 35.
    Weiner, S.J., Kollman, P.A., Nguyen, D.T. and Case, D.A., J. Comput. Chem., 7 (1986) 230.Google Scholar
  36. 36.
    Poulos, T.L. and Howard, A.J., Biochemistry, 26 (1987) 8165.Google Scholar
  37. 37.
    Gaussian 94, Revision E.1, Frisch, M.J., Trucks, G.W., Schlegel, H.B., Gill, P.M.W., Johnson, B.G., Robb, M.A., Cheeseman, J.R., Keith, T., Petersson, G.A., Montgomery, J.A., Raghavachari, K., Al-Laham, M.A., Zakrzewski, V.G., Ortiz, J.V., Foresman, J.B., Cioslowski, J., Stefanov, B.B., Nanayakkara, A., Challacombe, M., Peng, C.Y., Ayala, P.Y., Chen, W., Wong, M.W., Andres, J.L., Replogle, E.S., Gomperts, R., Martin, R.L., Fox, D.J., Binkley, J.S., Defrees, D.J., Baker, J., Stewart, J.P., Head-Gordon, M., Gonzalez, C. and Pople, J.A., Gaussian, Inc., Pittsburgh, PA, 1995.Google Scholar
  38. 38.
    Bayly, C.I., Cieplak, P., Cornell, W.D. and Kollman, P.A., J. Phys. Chem., 97 (1993) 10269.Google Scholar
  39. 39.
    Pastor, M., Cruciani, G. and Clementi, S., J. Med. Chem., 40 (1997) 1455.Google Scholar
  40. 40.
    Gotoh, O., J. Biol. Chem., 267 (1993) 83.Google Scholar
  41. 41.
    Furuya, H., Shimizu, T., Hirano, K., Hatano, M. and Fujii-Kuriyama, Y., Biochemistry, 28 (1989) 6848.Google Scholar
  42. 42.
    Shimizu, T., Sadeque, A.J.M., Sadeque, G.N., Hatano, M. and Fujii-Kuriyama, Y., Biochemistry, 30 (1991) 1490.Google Scholar
  43. 43.
    Tuck, F.S., Hiroya, K., Shimizu, T., Hatano, M. and Ortiz de Montellano, P.R., Biochemistry, 32 (1993) 2548.Google Scholar
  44. 44.
    Krainev, A.G., Shimizu, T., Ishigooka, M., Hiroya, K. and Hatano, M., Biochemistry, 32 (1993) 1951.Google Scholar
  45. 45.
    Poulos, T.L., Curr. Opin. Struct. Biol., 5 (1995) 767.Google Scholar
  46. 46.
    Oprea, T.I., Hummer, G. and Garcia, A.E., Proc. Natl. Acad. Sci. USA, 94 (1997) 2133.Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Juan José Lozano
    • 1
  • Manuel Pastor
    • 2
  • Gabriele Cruciani
    • 2
  • Katrin Gaedt
    • 1
  • Nuria B. Centeno
    • 1
  • Federico Gago
    • 3
  • Ferran Sanz
    • 1
  1. 1.Research Group on Medical Informatics, IMIMBarcelonaSpain
  2. 2.Laboratory on Chemometrics, Department of ChemistryUniversità di PerugiaPerugiaItaly
  3. 3.Department of PharmacologyUniversidad de AlcaláMadridSpain

Personalised recommendations