Journal of Computer-Aided Molecular Design

, Volume 18, Issue 11, pp 683–696 | Cite as

Docking studies on NSAID/COX-2 isozyme complexes using Contact Statistics analysis

  • Giuseppe Ermondi
  • Giulia Caron
  • Raelene Lawrence
  • Dario Longo
Article

Summary

The selective inhibition of COX-2 isozymes should lead to a new generation of NSAIDs with significantly reduced side effects; e.g. celecoxib (Celebrex®) and rofecoxib (Vioxx®). To obtain inhibitors with higher selectivity it has become essential to gain additional insight into the details of the interactions between COX isozymes and NSAIDs. Although X-ray structures of COX-2 complexed with a small number of ligands are available, experimental data are missing for two well-known selective COX-2 inhibitors (rofecoxib and nimesulide) and docking results reported are controversial. We use a combination of a traditional docking procedure with a new computational tool (Contact Statistics analysis) that identifies the best orientation among a number of solutions to shed some light on this topic.

Keywords

celecoxib Contact Statistics analysis COX-2 docking flurbiprofen MOE nimesulide NSAIDs rofecoxib 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Dannhardt, G., Kiefer, W. 2001Eur. J. Med. Chem.,36109Google Scholar
  2. Kurumbail, R.G., Kiefer, J.R., Marnett, L.J. 2001Curr. Opin. Struct. Biol.,11752Google Scholar
  3. Marnett, L.J., Kalgutkar, A.S. 1999Trends Pharmacol. Sci.,20465Google Scholar
  4. Hinz, B., Brune, K. 2002J. Pharmacol. Exp. Ther.,300367Google Scholar
  5. Loll, P.J., Garavito, R.M., Carrell, C.J., Carrell, H.L. 1996Acta Crystallogr. Sect. C–Cryst. Struct. Commun.,52455Google Scholar
  6. Kurumbail, R.G., Stevens, A.M., Gierse, J.K., McDonald, J.J., Stegeman, R.A., Pak, J.Y., Gildehaus, D., Miyashiro, J.M., Penning, T.D., Seibert, K., Isakson, P.C., Stallings, W.C. 1996Nature,384644Google Scholar
  7. Flower, R.J. 2003Nat. Rev. Drug Discov.,2179Google Scholar
  8. Llorens, O., Perez, J.J., Palomer, A., Mauleon, D. 2002J. Mol. Graph. Model.,20359Google Scholar
  9. Garcia-Nieto, R., Perez, C., Gago, F. 2000J. Comput.-Aided Mol. Des.,14147Google Scholar
  10. Taylor, R.D., Jewsbury, P.J., Essex, J.W. 2002J. Comput.-Aided Mol. Des.,16151Google Scholar
  11. Schulz-Gasch, T., Stahl, M. 2003J. Mol. Mod.,947Google Scholar
  12. Wang, R.X., Lu, Y.P., Wang, S.M. 2003J. Med. Chem.,462287Google Scholar
  13. Ferrara, P., Gohlke, H., Price, D.J., Klebe, G., Brooks, C.L. 2004J. Med. Chem.,473032Google Scholar
  14. Muegge, I., Martin, Y.C. 1999J. Med. Chem.,42791Google Scholar
  15. Bruno, I.J., Cole, J.C., Lommerse, J.P.M., Rowland, R.S., Taylor, R., Verdonk, M.L. 1997J. Comput.-Aided Mol. Des.,11525Google Scholar
  16. Ermondi, G., Lorenti, M., Caron, G. 2004J. Med. Chem.,473949Google Scholar
  17. Gohlke, H., Hendlich, M., Klebe, G. 2000J. Mol. Biol.,295337Google Scholar
  18. Christensen, I.T., Jorgensen, F.S. 1997J. Comput.-Aided Mol. Des.,11385Google Scholar
  19. Auffinger, P., Wipff, G. 1990J. Comput. Chem.,1119Google Scholar
  20. Holtje, H.D., Sippl, W. and Rognan, D., Molecular Modeling: Basic Principles and Applications, Wiley-CH, Weinheim, 2003, p. 35.Google Scholar
  21. Caron, G., Gaillard, P., Carrupt, P.A., Testa, B. 1997Helv. Chim. Acta,80449Google Scholar
  22. Altomare, C., Carrupt, P.A., Gaillard, P., El Tayar, N., Testa, B., Carotti, A. 1992Chem. Res. Toxicol.,5366Google Scholar
  23. Gaillard, P., Carrupt, P.A., Testa, B. 1994Bioorg. Med. Chem. Lett.,4737Google Scholar
  24. Ermondi, G., Caron, G., Bouchard, G., van Balen, G.P., Pagliara, A., Grandi, T., Carrupt, P.A., Fruttero, R., Testa, B. 2001Helv. Chim. Acta,84360Google Scholar
  25. Accelrys, Extensible Systematic Force Field, San Diego, CA, 1994.Google Scholar
  26. Trummlitz, G., van Ryn, J. 2002Curr. Opin. Drug Discov. Dev.,5550Google Scholar
  27. Filipponi, E., Cecchetti, V., Tabarrini, O., Bonelli, D., Fravolini, A. 2000J. Comput.-Aided Mol. Des.,14277Google Scholar
  28. Christensen, I.T., Jorgensen, F.S. 1997J. Biomol. Struct. Dyn.,15473Google Scholar
  29. Plount Price, M.L., Jorgensen, W.L. 2000J. Am. Chem. Soc.,1229455Google Scholar
  30. Holtje, H.D., Sippl, W. and Rognan, D., Molecular Modeling: Basic Principles and Applications, Wiley-CH, Weinheim, 2003, p. 129.Google Scholar
  31. Sadowski, J., Gasteiger, J., Klebe, G. 1994J. Chem. Inf. Comput. Sci.,341000Google Scholar
  32. Halgren, T.A. 1996J. Comput. Chem.,17490Google Scholar
  33. Chemical Computing Group Inc., Version 2003.02 (2003).Google Scholar
  34. Labute, P., J. Chem. Comput. Group, http://www.chemcomp.com/Journal_of_CCG/Features/cstat.htm (2003).Google Scholar
  35. Dixon, J.S., Proteins Struct. Funct. Genet., S1 (1997) 198.Google Scholar
  36. Rowlinson, S.W., Kiefer, J.R., Prusakiewicz, J.J., Pawlitz, J.L., Kozak, K.R., Kalgutkar, A.S., Stallings, W.C., Kurumbail, R.G., Marnett, L.J. 2003J. Biol. Chem.,27845763Google Scholar
  37. Rafols, C., Roses, M., Bosch, E. 1997Anal. Chim. Acta,338127Google Scholar
  38. Ippolito, J.A., Christianson, D.W. 1992Int. J. Biol. Macromol.,14193Google Scholar
  39. Talley, J.J. 1999Prog. Med. Chem.,36201Google Scholar
  40. Fallavena, P.R.B., Schapoval, E.E.S. 1997Int. J. Pharm.,158109Google Scholar
  41. Marnett, L.J., Rowlinson, S.W., Goodwin, D.C., Kalgutkar, A.S., Lanzo, C.A. 1999J. Biol. Chem.,27422903Google Scholar
  42. Greig, G.M., Francis, D.A., Falgueyret, J.P., Ouellet, M., Percival, M.D., Roy, P., Bayly, C., Mancini, J.A., ONeill, G.P. 1997Mol. Pharmacol.,52829Google Scholar
  43. Chavatte, P., Yous, S., Marot, C., Baurin, N., Lesieur, D. 2001J. Med. Chem.,443223Google Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Giuseppe Ermondi
    • 1
  • Giulia Caron
    • 1
  • Raelene Lawrence
    • 2
  • Dario Longo
    • 3
  1. 1.Dipartimento di Scienza e Tecnologia del FarmacoTorinoItaly
  2. 2.Chemical Computing Group, Inc.Montreal, QuebecCanada
  3. 3.Bioindustry Park del CanaveseColleretto Giacosa (TO)Italy

Personalised recommendations