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Journal of Computer-Aided Molecular Design

, Volume 14, Issue 3, pp 277–291 | Cite as

Chemometric rationalization of the structural and physicochemical basis for selective cyclooxygenase-2 inhibition: Toward more specific ligands

  • Enrica Filipponi
  • Violetta Cecchetti
  • Oriana Tabarrini
  • Daniela Bonelli
  • Arnaldo Fravolini
Article

Abstract

The discovery that proinflammatory prostaglandins are produced by cyclooxygenase-2 (COX-2), an inducible isoform of the constitutive cyclooxygenase-1 (COX-1), opened a new frontier in the treatment of inflammatory diseases, because the selective inhibition of COX-2 can lead to therapeutically effective compounds which do not have the common side effects of classical non-steroidal antiinflammatory drugs (NSAIDs). Different crystallographic structures of both free COX-1 and COX-2 as well as complexes with inhibitors have been solved. Because of the great similarity between the two enzymes, it is difficult to detect the most important structural and physicochemical features that would be useful for designing inhibitors with an improved selectivity. In this paper we describe the application of a chemometric procedure to the study of COX-2 selective inhibition. This method, developed to reveal the most suitable regions of isoenzymes for the design of selective ligands, also has a very practical utility. GRID multivariate characterization of the enzymes and subsequent Principal Component Analysis (PCA) of the descriptor variables allow the identification of chemical groups that could be added to a core template structure to increase ligand selectivity.

cyclooxygenase-2 GRID characterization principal component analysis (PCA) selectivity 

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References

  1. 1. a.
    Vane, J.R., Nature (New Biol.), 231 (1971) 232.Google Scholar
  2. 1. b.
    Smith, J.B. and Willis, A.L., Nature (New Biol.), 231 (1971) 235.Google Scholar
  3. 2.
    Vane, J.R., Mitchell, J.A., Appleton, I., Tomlinson, A., Bishop-Bailey, D., Croxtail, J. and Willoughby, D.A., Proc. Natl. Acad. Sci. USA, 91 (1994) 2046.PubMedGoogle Scholar
  4. 3. a.
    Hla, T. and Neilson, K., Proc. Natl. Acad. Sci. USA, 89 (1992) 7384.PubMedGoogle Scholar
  5. 3. b.
    Xie, W., Chipman, J.G., Robertson, D.L., Erokson, R.L. and Simmons, D.L., Proc. Natl. Acad. Sci. USA, 88 (1991) 2692.PubMedGoogle Scholar
  6. 3. c.
    Kujubu, D.A., Fletcher, B.S., Varnum, B.C., Lim, R.W. and Herschman, H.R., J. Biol. Chem., 14 (1971) 1171.Google Scholar
  7. 4. a.
    Masferrer, J.L., Zweifel, B.S., Manning, P.T., Hauser, S.D., Leahey, K.M., Smith, W.G., Isakson, P.C. and Seibert, K., Proc. Natl. Acad. Sci. USA, 91 (1994) 3228.PubMedGoogle Scholar
  8. 4. b.
    Seibert, K. and Masferrer, J.L., Receptor, 4 (1994) 17.PubMedGoogle Scholar
  9. 4. c.
    Meade, E.A., Smith, V.L. and DeWitt, D.L., J. Biol. Chem., 268 (1993) 6610.PubMedGoogle Scholar
  10. 4. d.
    Mitchell, J.A., Akarasereemont, P., Thiemerman, C., Flower, R.J. and Wane, J.R., Proc. Natl. Acad. Sci. USA, 90 (1993) 11693.PubMedGoogle Scholar
  11. 4. e.
    Harada, Y., Hatanaka, K., Saito, M., Majima, M., Ogina, M., Kawamura, M., Ohno, T., Yang, Q., Katori, M. and Yamamoto, S., Biomed. Res., 15 (1994) 127.Google Scholar
  12. 5. a.
    Vane, J.R., Nature, 367 (1994) 215.PubMedGoogle Scholar
  13. 5. b.
    Vane, J.R. and Botting, R.M., Inflamm. Res., 44 (1995) 1.PubMedGoogle Scholar
  14. 5.c.
    DeWitt, D.L., Meade, E.A. and Smith, V.L., Am. J. Med., 95 (1993) 2A-40S.Google Scholar
  15. 6.
    Wallance, J.L., TIPS, 20 (1999) 4.PubMedGoogle Scholar
  16. 7.
    Picot, D., Loll, P.J. and Garavito, M., Nature, 367 (1994) 243.PubMedGoogle Scholar
  17. 8.
    Kurumbail, R.G., Stevens, A.M., Gierse, J.K., McDonald, J.J., Stegeman, R.A., Pak, J.Y., Gildehaus, D., Miyshiro, J.M., Penning, T.D., Seibert, K., Isakson, P.C. and Stallings, W.C., Nature, 384 (1996) 644.Google Scholar
  18. 9.
    Luong, C., Miller, A., Barnett, J., Chow, J., Ramesha, C. and Browner, M.F., Nature Struct. Biol., 3 (1996) 927.PubMedGoogle Scholar
  19. 10.
    Gierse, J.K., McDonald, J.J., Hauser, S.D., Rangwala, S.H., Koboldt, C.M. and Seibert, K., J. Biol. Chem., 271 (1996) 15810.PubMedGoogle Scholar
  20. 11.
    Quipeng, G., Lee-Ho, W., Ke-He, R. and Richard, J.K., J. Biol. Chem., 271 (1996) 19134.PubMedGoogle Scholar
  21. 12.
    Futaki, N., Takahashi, S., Yokoyama, M., Arai, I. and Higuchi, S., Prostaglandins, 47 (1994) 55.PubMedGoogle Scholar
  22. 13.
    Swingle, K.F., Moore, G.G.I. and Grant, T.J., Arch. Int. Pharmacodyn., 221 (1976) 132.PubMedGoogle Scholar
  23. 14.
    Gans, K.R., Galbraith, W., Roman, R.J., Haber, S.B., Kerr, J.S., Schmidt, W.K., Smith, C., Hewes, W.E. and Ackerman, N.R., J. Pharmacol. Exp. Ther., 254 (1990) 180.PubMedGoogle Scholar
  24. 15.
    Seibert, K., Zhang, Y., Leahy, K., Hauser, S., Masferrer, J., Perkins, W., Lee, L. and Isakson, P., Proc. Natl. Acad. Sci. USA, 91 (1994) 12013.PubMedGoogle Scholar
  25. 16.
    Penning, T.D., Talley, J.J., Bertenshaw, S.R., Carter, J.S., Collins, P.W., Docter, S., Matthew, J.G., Lee, L.F., Malecha, J.W., Miyashiro, J.M., Rogers, R.S., Rogier, D.J., Yu, S.S., Anderson, G.D., Burton, E.G., Cogburn, J.N., Gregory, S.A., Koboldt, C.M., Perkins, W.E., Veenhuizen, A.W., Zhang, Y.Y. and Isakson, P.C., J. Med. Chem., 40 (1997) 1347.PubMedGoogle Scholar
  26. 17. a.
    Pouplana, R., Perez, C., Sanchez, J., Lozano, J.J. and Puig-Parellada, P., J. Comput.-Aided Mol. Design, 13 (1999) 287.Google Scholar
  27. 17. b.
    Gabriel, F.F., Vasantha, P. and Kuppuswamy, N., Bioorg. Med. Chem., 6 (1998) 2337.PubMedGoogle Scholar
  28. 17. c.
    Pedretti, A., Villa, A.M., Villa, L. and Vistoli, G., Il Farmaco, 52 (1997) 487.PubMedGoogle Scholar
  29. 17. d.
    Stewart, K.D., Loren, S., Frey, L., Otis, E., Klinghofer, V. and Hulkower, K., Bioorg. Med. Chem. Lett., 8 (1998) 529.PubMedGoogle Scholar
  30. 18. a.
    Cruciani, G. and Goodford, P.J., J. Mol. Graphics, 12 (1994) 116.Google Scholar
  31. 18. b.
    Pastor, M. and Cruciani, G., J. Med. Chem., 38 (1995) 4637.PubMedGoogle Scholar
  32. 18. c.
    Matter, H. and Schwab, E., J. Med. Chem., 42 (1999) 4506.PubMedGoogle Scholar
  33. 19.
    Goodford, P.J., J. Med. Chem., 28 (1985) 849.PubMedGoogle Scholar
  34. 20.
    GRID v.16 Manuals, Molecular Discovery Ltd.Google Scholar
  35. 21.
    Wold, S., Esbensen, K. and Geladi, P., Chemom. Intell. Lab. Syst., 2 (1987) 37.Google Scholar
  36. 22.
    Brookhaven National Laboratories Protein Databank.Google Scholar
  37. 23.
    SYBYL 6.3 Molecular Modeling Software, Tripos, Inc.Google Scholar
  38. 24.
    Baroni, M. and Pastor, M., GOLPE v. 4.0.2, Multivariate Infometric Analysis 1998.Google Scholar
  39. 25. a.
    Cruciani, G., Baroni, M., Clementi, S., Costantino, G., Riganelli, D. and Skagerberg, B., J. Chemometrics, 6 (1992) 335.Google Scholar
  40. 25. b.
    Wold, S., Technometrics, 20 (1978) 397.Google Scholar
  41. 26.
    WO96/09304 PCT/US95/11403.Google Scholar
  42. 27.
    Loll, P.J., Picot, D. and Garavito, R.M., Nat. Struct. Biol., 2 (1995) 639.Google Scholar

Copyright information

© Kluwer Academic Publishers 2000

Authors and Affiliations

  • Enrica Filipponi
    • 1
  • Violetta Cecchetti
    • 1
  • Oriana Tabarrini
    • 1
  • Daniela Bonelli
    • 2
  • Arnaldo Fravolini
    • 1
  1. 1.Istituto di Chimica e Tecnologia del FarmacoUniversità di PerugiaPerugiaItaly
  2. 2.Dipartimento di ChimicaUniversità di PerugiaPerugiaItaly

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