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Automated docking and molecular dynamics simulations of nimesulide in the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 (COX-2)

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Abstract

Molecular models of the complex between the selective COX-2 inhibitor nimesulide and the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 have been built using a combination of homology modelling, conformational searching and automated docking techniques. The stability of the resulting complexes has been assessed by molecular dynamics simulations and interaction energy decomposition. It is found that nimesulide exploits the extra space made available by the replacement at position 523 of an isoleucine residue in COX-1 by a valine in COX-2 and establishes electrostatic interactions with both Arg-106 and Arg-499 (Arg-120 and Arg-513 in PGHS-1 numbering). Two alternate binding modes are proposed which are compatible with the pharmacological profile of this agent as a COX-2 selective inhibitor.

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References

  1. Vane, J.R., Bakhie, Y.S. and Botting, R.M., Annu. Rev. Pharmacol. Toxicol., 38 (1998) 97.

    Google Scholar 

  2. Spencer, A.G., Woods, J.W., Arakawa, T., Singer I.I. and Smith, W.L., J. Biol. Chem., 273 (1998) 9886.

    Google Scholar 

  3. Meade, E.A., Smith, W.L. and DeWitt, D.L., J. Biol. Chem., 268 (1993) 6610.

    Google Scholar 

  4. Laneuville, O., Breuer, D.K., Dewitt, D.L., Hia, T., Funk, C.D. and Smith, W.L., J. Pharmacol. Exp. Ther., 271 (1994) 927.

    Google Scholar 

  5. Riendeau, D., Charieson, S., Cromlish, W., Mancini, J.A., Wong, E. and Guay, J., Can. J. Physiol. Pharmacol., 75 (1997) 1088.

    Google Scholar 

  6. Copeland, R.A., Williams, J.M., Giannaras, J., Nurnberg, S., Covington, M., Pinto, D., Pick, S. and Trzaskos, J.M., Proc. Natl. Acad. Sci. USA, 91 (1994) 91, 11202.

    Google Scholar 

  7. Khanna, I.K., Weier, R.M., Yu, Y., Xu, X.D., Koszyk, F.J., Collins, P.W., Koboldt, C.M., Veenhuizen, A.W., Perkins, W.E., Casier, J.J., Masferrer, J.L., Zhang, Y.Y., Gregory, S.A., Seibert, K. and Isakson, P.C., J. Med. Chem., 40 (1997) 1634.

    Google Scholar 

  8. Khanna, I.K., Weier, R.M., Yu, Y., Collins, P.W., Miyashiro, J.M., Koboldt, C.M., Veenhuizen, A.W., Currie, J.L., Seibert, K. and Isakson, P.C., J. Med. Chem., 40 (1997) 1619.

    Google Scholar 

  9. Penning, T.D., Talley, J.J., Bertenshaw, S.R., Carter, J.S., Collins, P.W., Docter, S., Graneto, M.J., 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., Seibert, K., Veenhuizen, A.W., Zhang, Y.Y. and Isakson, P.C., J.Med. Chem., 40 (1997) 1347.

    Google Scholar 

  10. Kalgutkar, A.S., Kozak, K.R., Crews, B.C., Hochgesang, G.P.</del>Jr. and Marnett, L.J., J. Med. Chem., 41 (1998) 4800.

    Google Scholar 

  11. Picot, D., Loll, P.J. and Garavito, R.M., Nature, 367 (1994) 243.

    Google Scholar 

  12. Loll, P.J., Picot, D., Ekabo, O. and Garavito, R.M., Biochemistry, 35 (1996) 7330.

    Google Scholar 

  13. Loll, P.J., Picot, D. and Garavito, R.M., Nat. Struct. Biol., 2 (1995) 637.

    Google Scholar 

  14. Luong, C., Miller, A., Barnett, J., Chow, J., Ramesha, C. and Browner, M.F., Nat. Struct. Biol., 3 (1996) 927.

    Google Scholar 

  15. 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. and Stailings, W.C., Nature, 384 (1996) 644.

    Google Scholar 

  16. Marnett, L.J. and Kaigutkar, A.S., Curr. Opin. Chem. Biol., 4 (1998) 482.

    Google Scholar 

  17. Swingle, K.F., Moore, G.G.I. and Grant, T.J., Arch. Int. Pharmacodyn., 221 (1976) 132.

    Google Scholar 

  18. Famaey, J.P., Inflamm. Res., 46 (1997) 437.

    Google Scholar 

  19. Cullen, L., Kelly, L., Connor, S.O. and Fitzgerald, D.J., J. Pharmacol. Exp. Ther., 287 (1998) 578.

    Google Scholar 

  20. Panara, M.R., Padovano, R., Sciuii, M.G., Santini, G., Renda, G., Rotondo, M.T., Pace, A., Patrono, C. and Patrignani, P., Clin. Pharmacol. Ther., 63 (1998) 672.

    Google Scholar 

  21. Hardman, J.G., Gilman, A.G. and Limbird, L.E. (Eds.) Goodman & Gilman' The Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, New York, NY, 1996.

    Google Scholar 

  22. Vigdahl, R.L. and Tukey, R.H., Biochem. Pharmacol., 126 (1977) 307.

    Google Scholar 

  23. García-Nieto, R., Pérez, C., Checa, A. and Gago, F., 11th EULAR Symposium, Geneva, Switzerland, September 5–8, 1998.

  24. Bernstein, F.C., Koetzle, T.F., Williams, G.J.B., Meyer, E.F. Jr., Brice, M.D., Rodgers, J.R., Kennard, O., Shimanouchi, T. and Tasumi, M., J. Mol. Biol., 112 (1977) 535.

    Google Scholar 

  25. Insight II, version 97.2, 1998. Molecular Simulations Inc., San Diego, CA.

  26. Pearlman, D.A., Case, D.A., Caldwell, J., Ross, W.S., Cheatham, T.E., Ferguson, D.M., Seibel, G.L., Singh, U.C., Weiner, P. and Kollman, P.A., AMBER version 4.1 (1995), Department of Pharmaceutical Chemistry, University of California, San Francisco, CA.

    Google Scholar 

  27. Dupont, L., Pirotte, B., Masereel, B., Delarge, J. and Geczy, J., Acta Crystallogr., C51 (1995) 507.

    Google Scholar 

  28. Allen, F.H., Bellard, S., Brice, M.D., Cartwright, B.A., Doubleday, A., Higgs, H., Hummelink, T., Hummelink-Peters, B.G., Kennard, O., Motherwell, W.D.S., Rodgers, J.D. and Watson, D.G., Acta Crystallogr., B35 (1979) 2331.

    Google Scholar 

  29. 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 

  30. Besler, B.H., Merz, K.M. and Kollman, P.A., J. Comput. Chem., 11 (1990) 431.

    Google Scholar 

  31. Cornell, W.D., Cieplak, P., Bayly, C.I., Gould, I.R., Merz, K.M., Ferguson, D.M., Spellmeyer, D.C., Fox, T., Caldwell, J.W. and Kollman, P.A., J. Am. Chem. Soc., 117 (1995) 5179.

    Google Scholar 

  32. GRIN, GRID, GRAB, and GROUP version 16.0, Molecular Discovery Ltd., 1998.

  33. DOCK, version 3.5, Molecular Design Institute, University of California, San Francisco, CA, 1995.

  34. Connolly, M.L., J. Appl. Crystallogr., 16 (1983) 548.

    Google Scholar 

  35. Kuntz, I.D., Blaney, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.

    Google Scholar 

  36. AutoDock: Automated Docking of Flexible Ligands to Receptors, Version 2.4 (1996), Morris, G.M., Goodsell, D.S., Huey, R. and Olson, A.J., The Scripps Research Institute, La Jolla, CA.

    Google Scholar 

  37. Warwicker, J. and Watson H.C., J. Mol. Biol., 157 (1982) 671.

    Google Scholar 

  38. Honig, B. and Nicholls, A., Science, 268 (1995) 1144.

    Google Scholar 

  39. Checa, A., Ortiz, A.R., de Pascual-Teresa, B. and Gago, F., J. Med. Chem., 40 (1997) 4136.

    Google Scholar 

  40. Futaki, N., Takahashi, S., Yokoyama, M., Arai, I., Higuchi, S. and Otomo, S., Prostaglandins, 47 (1994) 55.

    Google Scholar 

  41. Harada, Y., Kawamura, M., Hatanaka, K., Saito, M., Ogino, M., Ohno, T., Ogino, K. and Yang, Q., Prostaglandins Other Lipid. Mediat., 55 (1998) 345.

    Google Scholar 

  42. Li, C.S., Black, W.C., Chan, C.C., Ford-Hutchinson, A.W., Gauthier, J.Y., Gordon, R., Guay, D., Kargman, S., Lau, C.K., Mancini, J., Ouimet, N., Roy, P., Vickers, P., Wong, E., Young, R.N., Zamboni, R. and Prasit, P., J. Med. Chem., 38 (1995) 4897.

    Google Scholar 

  43. Vago, T., Arzneimittelforschung, 45 (1995) 1096.

    Google Scholar 

  44. Ouellet, M. and Percival, M.D., Biochem J., 306 (1995) 247.

    Google Scholar 

  45. Guo, Q., Wang, L.H., Ruan, K.H. and Kulmacz, R.J., J. Biol. Chem., 271 (1996) 19134.

    Google Scholar 

  46. Wong, E., Bayly, C., Waterman, H.L., Riendeau, D. and Mancini, J.A., J. Biol. Chem., 272 (1997) 9280.

    Google Scholar 

  47. Gierse, J.K., McDonald, J.J., Hauser, S.D., Rangwala, S.H., Koboldt, C.M. and Seibert, K., J. Biol. Chem., 271 (1996) 15810.

    Google Scholar 

  48. Mancini, J.A., Vickers, P.J., O'Neill, G.P., Boily, C., Falgueyret, J.P. and Riendeau, D., Mol. Pharmacol., 51 (1997) 52.

    Google Scholar 

  49. Mancini, J.A., Riendeau, D., Falgueyret, J.P., Vickers, P.J. and O'Neill, G.P., J. Biol. Chem., 270 (1995) 29372.

    Google Scholar 

  50. Greig, G.M., Francis, D.A., Falgueyret, J.P., Ouellet, M., Percival, M.D., Roy, P., Bayly, C., Mancini, J.A. and O'Neill, G.P., Mol. Pharmacol., 52 (1997) 829.

    Google Scholar 

  51. Bhattacharyya, D.K., Lecomte, M., Rieke, C.J., Garavito, M. and Smith, W.L., J. Biol. Chem., 271 (1996) 2179.

    Google Scholar 

  52. So, O.Y., Scarafia, L.E., Mak, A.Y., Callan, O.H. and Swinney, D.C., J. Biol. Chem., 273 (1998) 5801.

    Google Scholar 

  53. Cignarella, G., Vianello, P., Berti, F. and Rossoni, G., Eur. J. Med. Chem., 31 (1996) 359.

    Google Scholar 

  54. Hendlich, M., Rippmann, F. and Barnickel, G. (unpublished), The ReLiBase System (Version 2.5), http://www2.ebi.ac.uk:8081/readme2.html.

  55. Fukutake, M., Nakatsugi, S., Isoi, T., Takahashi, M., Ohta, T., Mamiya, S., Taniguchi, Y., Sato, H., Fukuda, K., Sugimura, T. and Wakabayashi, K., Carcinogenesis, 19 (1998) 1939.

    Google Scholar 

  56. Okajima, E., Denda, A., Ozono, S., Takahama, M., Akai, H., Sasaki, Y., Kitayama, W., Wakabayashi, K. and Konishi, Y., Cancer Res., 58 (1998) 3028.

    Google Scholar 

  57. Pedretti, A., Villa, A.M., Villa, L. and Vistoli, G., Farmaco, 52 (1997) 487.

    Google Scholar 

  58. Fabiola, G.F., Pattabhi, V. and Nagarajan, K., Bioorg. Med. Chem., 6 (1998) 2337.

    Google Scholar 

  59. Kollman, P., Chem. Rev., 93 (1993) 2395.

    Google Scholar 

  60. Åqvist, J., Medina, C. and Samuelsson, J.-E., Protein Eng., 7 (1994) 385.

    Google Scholar 

  61. Corpet, F., Nucleic Acids Res., 16 (1988) 10881.

    Google Scholar 

  62. SMOOFT routine, In Press, W.H., Flannery, B.P., Teukolsky, S.A. and Vetterling, W.T. (Eds.) Numerical Recipes, Cambridge University Press, Cambridge, U.K., 1989.

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García-Nieto, R., Pérez, C. & Gago, F. Automated docking and molecular dynamics simulations of nimesulide in the cyclooxygenase active site of human prostaglandin-endoperoxide synthase-2 (COX-2). J Comput Aided Mol Des 14, 147–160 (2000). https://doi.org/10.1023/A:1008110924479

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