Journal of Computer-Aided Molecular Design

, Volume 17, Issue 11, pp 739–754 | Cite as

Molecular modelling studies on the ORL1-receptor and ORL1-agonists

  • Britta M. Bröer
  • Marion Gurrath
  • Hans-Dieter Höltje


The ORL1 (opioid receptor like 1)- receptor is a member of the family of rhodopsin-like G protein-coupled receptors (GPCR) and represents an interesting new therapeutical target since it is involved in a variety of biomedical important processes, such as anxiety, nociception, feeding, and memory. In order to shed light on the molecular basis of the interactions of the GPCR with its ligands, the receptor protein and a dataset of specific agonists were examined using molecular modelling methods. For that purpose, the conformational space of a very potent non-peptide ORL1-receptor agonist (Ro 64-6198) with a small number of rotatable bonds was analysed in order to derive a pharmacophoric arrangement. The conformational analyses yielded a conformation that served as template for the superposition of a set of related analogues. Structural superposition was achieved by employing the program FlexS. Using the experimental binding data and the superposition of the ligands, a 3D-QSAR analysis applying the GRID/GOLPE method was carried out. After the ligand-based modelling approach, a 3D model of the ORL1-receptor has been constructed using homology modelling methods based on the crystal structure of bovine rhodopsin. A representative structure of the model taken from molecular dynamics simulations was used for a manual docking procedure. Asp-130 and Thr-305 within the ORL1-receptor model served as important hydrophilic interaction partners. Furthermore, a hydrophobic cavity was identified stabilizing the agonists within their binding site. The manual docking results were supported using FlexX, which identified the same protein-ligand interaction points.

binding site docking 3D-QSAR GPCR molecular modelling ORL1-receptor pharmacophore receptor model 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Mollereau, C., Parmentier, M., Mailleux, P., Butour, J.-L., Moisand, C., Chalon, P., Caput, D., Vassart, G. and Meunier, J.-C., FEBS Lett., 341 (1994) 33.PubMedGoogle Scholar
  2. 2.
    Ronzoni, S., Peretto, I. and Giardina, G., Exp. Opin. Ther. Patents, 11 (2001) 525.Google Scholar
  3. 3.
    Meunier, J.C., Eur. J. Pharmacol., 340 (1997) 1.PubMedGoogle Scholar
  4. 4.
    Meunier, J.C., Exp. Opin. Ther. Patents, 10 (2000) 371.Google Scholar
  5. 5.
    Reinscheid, R.K., Nothacker, H.-P., Bourson, A., Ardati, A., Henningsen, R.A., Bunzow, J.R., Grandy, D.K., Langen, H., Monsma, F.J., Jr. and Civelli, O., Science, 270 (1995) 792.PubMedGoogle Scholar
  6. 6.
    Jenck, F., Wichmann, J., Dautzenberg, F.M., Moreau, J.-L., Ouagazzal, A.M., Martin, J.R., Lundstrom, K., Cesura, A.M., Poli, S.M., Röver, S., Kolczewski, S., Adam, G. and Kilpatrick, G., Proc. Natl. Acad. Sci. USA, 97 (2000) 4938.PubMedGoogle Scholar
  7. 7.
    Röver, S., Adam, G., Cesura, A.M., Galley, G., Jenck, F., Monsma, F.J., Jr., Wichmann, J. and Dautzenberg, F., J. Med. Chem., 43 (2000) 1329.PubMedGoogle Scholar
  8. 8.
    Röver, S., Wichmann, J., Jenck, F., Adam, G. and Cesura, A.M., Bioorg. Med. Chem. Lett., 10 (2000) 831.PubMedGoogle Scholar
  9. 9.
    Weiner, S. J., Kollman, P.A., Case, D.A., Singh, U.C., Ghio, C., Alagona, G., Profeta, S. and Weiner, P.J., J. Am. Chem. Soc., 106 (1984) 765.Google Scholar
  10. 10.
    FlexS: Lemmen, C., Lengauer, T. and Klebe, G., J. Med. Chem., 41 (1998) 4502.PubMedGoogle Scholar
  11. 11.
    Lemmen, C. and Lengauer, T., J. Comput.-Aided Mol. Des., 11 (1997) 357.PubMedGoogle Scholar
  12. 12.
    GRID, Version 20, Molecular Discovery Ltd., Oxford, UK.Google Scholar
  13. 13.
    GOLPE 4.5. Multivariate Infometric Analysis Srl., Perugia, Italy, 1999.Google Scholar
  14. 14.
    Cruciani, G. and Watson, K.A., J. Med. Chem., 37 (1994) 2589.PubMedGoogle Scholar
  15. 15.
    Pastor, M., Cruciani, G. and Clementi, S., J. Med. Chem., 40 (1997) 1455.PubMedGoogle Scholar
  16. 16.
    Baroni, M., Constantino, G., Cruciani, G., Riganelli, D, Va-ligli, R. and Clementi, S., Quant. Struct.-Act. Relat., 12 (1993) 9.Google Scholar
  17. 17.
    Oprea, T.I. and Garcia, A.E., J. Comput.-Aided Mol. Des., 10 (1996) 186.PubMedGoogle Scholar
  18. 18.
    Krystek, S.R., Hunt, J.T., Stein, P.D. and Stouch, T.R., J. Med. Chem., 38 (1995) 659.PubMedGoogle Scholar
  19. 19.
    Höltje, H.-D., Sippl, W., Rognan, D. and Folkers, G., Molecu-lar Modeling: Basic Principles and Applications, 2nd edition, Wiley-VCH Verlagsgesellschaft, Weinheim, Germany, 2003.Google Scholar
  20. 20.
    Palczewski, K., Kumasaka, T., Hori, T., Behnke, C.A., Mo-toshima, H., Fox, B.A., Le Trong, I., Teller, D.C., Okada, T., Stenkamp, R.E., Yamamoto, M. and Miyano, M., Science, 289 (2000) 739.Google Scholar
  21. 21.
    Insight II 2000, Accelrys Inc., San Diego, CA.Google Scholar
  22. 22.
    Rost, B., Casadio, R., Fariselli, P. and Sander, C., Protein Sci.,4 (1995) 521.PubMedGoogle Scholar
  23. 23.
    Rost, B., Fariselli, P. and Casadio, R., Protein Sci., 5 (1996) 1704.PubMedGoogle Scholar
  24. 24.
    Baldwin, J.M., Schertler, G.F.X. and Unger, V.M., J. Mol. Biol., 272 (1997) 144.PubMedGoogle Scholar
  25. 25.
    SCWRL: Dunbrack, R.L. and Cohen, F.E., Protein Sci., 6 (1997) 1661.PubMedGoogle Scholar
  26. 26.
    NMRCLUST: Kelley, L.A., Gardner, S.P. and Sutcliffe, M.J., Protein Eng., 9 (1996) 1063.PubMedGoogle Scholar
  27. 27.
    PROCHECK: Laskowski, R.A., MacArthur, M.W., Moss, D.S. and Thornton, J.M., J. Appl. Crystallogr., 26 (1993) 283.Google Scholar
  28. 28.
    FlexX: Kramer, B., Rarey, M. and Lengauer, T., Proteins, 37 (1999) 228.PubMedGoogle Scholar
  29. 29.
    Böhm, H.-J., J. Comput.-Aided Mol. Des., 6 (1992) 593.PubMedGoogle Scholar
  30. 30.
    Böhm, H.-J., J. Comput.-Aided Mol. Des., 8 (1994) 243.PubMedGoogle Scholar
  31. 31.
    Rarey, M., Kramer, B. and Lengauer, T., J. Comput.-Aided Mol. Des., 11 (1997) 369.PubMedGoogle Scholar
  32. 32.
    Mouledous, L., Topham, C.M., Moisand, C., Mollereau, C.and Meunier, J.-C., Mol. Pharmacol., 57 (2000) 495.PubMedGoogle Scholar
  33. 33.
    Thomsen, C. and Hohlweg, R., Br. J. Pharmacol., 131 (2000)Google Scholar
  34. 34.
    Kolczewski, S., Adam, G., Cesura, A.M., Jenck, F., Hennig, M., Oberhauser, T., Poli, S.M., Rössler, F., Röver, S., Wich-mann, J. and Dautzenberg, F.M., J. Med. Chem., 46 (2003)Google Scholar
  35. 35.
    Topham, C.M., Mouledous, M., Poda, G., Maigret, B. and Meunier, J.-C., Protein Eng., 11 (1998) 1163.PubMedGoogle Scholar
  36. 36.
    Meunier, J.-C., Mouledous, L. and Topham, C.M., Peptides, 21 (2000) 893.PubMedGoogle Scholar
  37. 37.
    Herzyk, P. and Hubbard, R.E., Biophys. J., 69 (1995) 2419.PubMedGoogle Scholar
  38. 38.
    Hindle, S.A., Rarey, M., Buning, C. and Lengauer, T., J. Comput.-Aided Mol. Des., 16 (2002) 129.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Britta M. Bröer
    • 1
  • Marion Gurrath
    • 1
  • Hans-Dieter Höltje
    • 1
  1. 1.Institute for Pharmaceutical ChemistryHeinrich-Heine-University DüsseldorfDüsseldorfGermany

Personalised recommendations