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Development of a unique 3D interaction model of endogenous and synthetic peripheral benzodiazepine receptor ligands

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Abstract

Different classes of Peripheral-type Benzodiazepine Receptor (PBR) ligands were examined and common structural elements were detected and used to develop a rational binding model based on energetically allowed ligand conformations. Two lipophilic regions and one electrostatic interaction site are essential features for high affinity ligand binding, while a further lipophilic region plays an important modulator role. A comparative molecular field analysis, performed over 130 PBR ligands by means of the GRID/GOLPE methodology, led to a PLS model with both high fitting and predictive values (r2 = 0.898, Q2 = 0.761). The outcome from the 3D QSAR model and the GRID interaction fields computed on the putative endogenous PBR ligands DBI (Diazepam Binding Inhibitor) and TTN (Tetracontatetraneuropeptide) was used to identify the amino acids most probably involved in PBR binding. Three amino acids, bearing lipophilic side chains, were detected in DBI (Phe49, Leu47 and Met46) and in TTN (Phe33, Leu31 and Met30) as likely residues underlying receptor binding. Moreover, a qualitative comparison of the molecular electrostatic potentials of DBI, TTN and selected synthetic ligands indicated also similar electronic properties. Convergent results from the modeling studies of synthetic and endogenous ligands suggest a common binding mode to PBRs. This may help the rational design of new high affinity PBR ligands.

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References

  1. Giesen-Crouse, E. (Ed.) Peripheral Benzodiazepine Receptor. Academic Press, London, 1993.

    Google Scholar 

  2. McEnery, M.W., Snowman, A.M., Trifiletti, R.R. and Snyder, S.H., Proc. Natl. Acad. Sci. USA, 89 (1992) 3170.

    Google Scholar 

  3. Liauzun, E.J., Farges, R., Delmas, P. and Ferrara, P., J. Biol. Chem., 272 (1997) 28102.

    Google Scholar 

  4. Wang, J.K.T., Taniguchi, T. and Spector, S., Mol. Pharmacol., 25 (1984) 349.

    Google Scholar 

  5. Zisterer, D.M. and Williams, D.C., Gen. Pharmacol., 29 (1997) 305.

    Google Scholar 

  6. Mukhin, A.G., Papadopoulos, V., Costa, E. and Krueger, K.E., Proc. Natl. Acad. Sci. U.S.A., 86 (1989) 9813.

    Google Scholar 

  7. Papadopoulos, V., Proc. Soc. Exp. Biol. Med., 217 (1998) 130.

    Google Scholar 

  8. Papadopoulos, V., Mukhin, A.G., Costa, E. and Krueger, K.E., J. Biol. Chem., 265 (1990) 3772.

    Google Scholar 

  9. Black, K.L., Ikezaki, K., Santori, E., Becker, D.P. and Vinters, H.V., Cancer, 65 (1990) 93.

    Google Scholar 

  10. Ikezaki, K., Black, K.L., Toga, A.W., Santori, E.M., Becker, D.P. and Smith, M.L., J. Cereb. Blood Flow Metab., 10 (1990) 580.

    Google Scholar 

  11. Kapezyk-Subotkowaka, L., Siahaan, T.J., Basile, A., Friedman, H.S., Higgins, P.E., Song, D. and Gallo, J.M., J. Med. Chem., 40 (1997) 1726.

    Google Scholar 

  12. Liao, Yi, Kozikowski, A.P., Guidotti, A. and Costa, E., Bioorg. Med. Chem. Lett., 8 (1998) 2099.

    Google Scholar 

  13. Schmitt, M., Bourguignon, J.-J., Barlin, G. and Les Davies, B., Aust. J. Chem., 50 (1997) 779.

    Google Scholar 

  14. Anzini, M., Cappelli, A., Vomero, S., Giorgi, G., Langer, T., Bruni, G., Romeo, M.R. and Basile, A., J. Med. Chem., 39 (1996) 4275.

    Google Scholar 

  15. Campiani, G., Fiorini, I., De Filippis, M., Ciani, S.M., Garofalo, A., Nacci, V., Giorgi, G., Sega, A., Botta, M., Chiarini, A., Budriesi, R., Bruni, G., Romeo, M.R., Manzoni, C. and Mennini, T., J. Med. Chem., 39 (1996) 2922.

    Google Scholar 

  16. Trapani, G., Franco, M., Ricciardi, L., Latrofa, A., Genchi, G., Sanna, E., Tuveri, F., Cagetti, E., Biggio, G. and Liso, G., J. Med. Chem., 40 (1997) 3109.

    Google Scholar 

  17. Trapani, G., Franco, M., Latrofa, A., Ricciardi, L., Carotti, A., Serra, M., Sanna, E., Biggio, G. and Liso, G., J. Med. Chem., 42 (1999) 3934.

    Google Scholar 

  18. Romeo, E., Auta, J., Kozikowski, A.P., Ma, D., Papadopoulos, V., Puia, G., Costa, E. and Guidotti, A., J. Pharm. Exp. Ther., 262 (1992) 971.

    Google Scholar 

  19. Okuyama, S., Chaki, S., Yoshikawa, R., Ogawa, S., Suzuki, Y., Okubo, T., Nakazato, A., Nagamine, M. and Tomisawa, K., Life Sci., 64 (1999) 1455.

    Google Scholar 

  20. Cappelli, A., Anzini, M., Vomero, S., De Benedetti, P.G., Menziani, M.C., Giorgi, G. and Manzoni, C., J. Med. Chem., 40 (1997) 2910.

    Google Scholar 

  21. Kozikowski, A.P., Kotoula, M., Ma, D., Boujrad, N., Tuckmantel, W. and Papadopoulos, V., J. Med. Chem., 40 (1997) 2435.

    Google Scholar 

  22. Raghavendra Rao, V.L. and Butterworth, R.F., Eur. J. Pharmacol., 340 (1997) 89.

    Google Scholar 

  23. Farges, R., Liauzun, E.J., Shire, D., Caput, D., Le Fur, G., Loison, G. and Ferrara, P., FEBS Lett., 335 (1993) 305.

    Google Scholar 

  24. Costa, E. and Guidotti, A., Life Sci., 49 (1991) 325.

    Google Scholar 

  25. Barbaccia, M.L., Costa, E. and Guidotti, A., Ann. Rev. Pharmacol. Toxicol., 28 (1988) 451.

    Google Scholar 

  26. Bercovich, A., Mcphie, P., Campagnone, M., Guidotti, A. and Hensley, P., Mol. Pharmacol., 37 (1989) 164.

    Google Scholar 

  27. Fiorini, I., Nacci, V., Ciani, S.M., Garofalo, A., Campiani, G., Savini, L., Novellino, E., Greco, G., Bernasconi, P. and Mennini, T., J. Med. Chem., 37 (1994) 1427.

    Google Scholar 

  28. Campiani, G., Nacci, V., Fiorini, I., De Filippis, M.P., Garofalo, A., Ciani, S.M., Greco, G., Novellino, E., Manzoni, C. and Mennini, T., J. Med. Chem., 32 (1997) 241.

    Google Scholar 

  29. Campiani, G., Nacci, V., Fiorini, I., De Filippis, M.P., Garofalo, A., Ciani, S.M., Greco, G., Novellino, E., Williams, D.C., Zisterer, D.M., Woods, M.J., Mihai, C., Manzoni, C. and Mennini, T., J. Med. Chem., 39 (1996) 3435.

    Google Scholar 

  30. Dalpiaz, A., Bertolasi, V., Borea, P.A., Nacci, V., Fiorini, I., Campiani, G., Mennini, T., Manzoni, C., Novellino, E. and Greco, G., J. Med. Chem., 38 (1995) 4730.

    Google Scholar 

  31. Greco, G., Novellino, E., Fiorini, I., Nacci, V., Campiani, G., Ciani, S.M., Garofalo, A., Bernasconi, P. and Mennini, T., J. Med. Chem., 37 (1994) 4100.

    Google Scholar 

  32. Cramer, R.D., Patterson, D.E. and Bunce, J.D., J. Am. Chem. Soc., 110 (1988) 5959.

    Google Scholar 

  33. 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.R. and Watson, D.G., Acta Crystallogr., B35 (1979) 2331.

    Google Scholar 

  34. TRIPOS Assoc., St. Louis, MO, U.S.A.

  35. Vinter, J.G., Davis, A. and Saunder, M.R., J. Comput.-Aided Mol. Design, 1 (1987) 31.

    Google Scholar 

  36. Olson, C. and Christoffersen, R.E. (Eds) Computer Assisted Drug Design, American Chemical Society Symposium 112, Washington, DC, 1979.

  37. Mikkelsen, J., Hojrup, P., Nielsen, P.F., Roepstorff, P. and Knudsen, J., Biochem. J., 245 (1987) 857.

    Google Scholar 

  38. Swinnen, J.V., Alen, P., Heyns, W. and Verhoeven, G., J. Biol. Chem., 273 (1998) 19938.

    Google Scholar 

  39. Andersen, K.V. and Poulsen, F.M., J. Mol. Biol., 226 (1992) 1131.

    Google Scholar 

  40. Kelley, L.A., Gardner, S.P. and Sutcliffe, M.J., Protein Eng., 9 (1996) 1063.

    Google Scholar 

  41. Kelley, L.A., Gardner, S.P. and Sutcliffe, M.J., Protein Eng., 10 (1997) 737.

    Google Scholar 

  42. Pullman, B. (Ed.) Intermolecular Forces, Proceedings of the Fourteenth Jerusalem Symposium on Quantum Chemistry and Biochemistry, D. Reidel Publ. Co., Dordrecht, 1981.

    Google Scholar 

  43. van der Spoel, D., van Buuren, A.R., Apol, E., Meulenhoff, P.J., Tielemann, D.P., Sijbers, A.L.T.M., van Drunen, R. and Berendsen, H.J.C., GROMACS manual, Bioson Research Institute and Laboratory of Biophysical Chemistry, University of Groningen, The Netherlands, 1996.

    Google Scholar 

  44. van Gunsteren, W.F. and Berendsen, H.J.C., Angew. Chem. Int. Ed. Engl., 29 (1990) 992.

    Google Scholar 

  45. Biosym Technologies Inc., San Diego, CA.

  46. Slobodyansky, E., Guidotti, A., Wambebe, C., Berkovich, A. and Costa, E., J. Neurochem., 53 (1989) 1276.

    Google Scholar 

  47. Burley, S.K. and Pesko, G.A., Science, 229 (1985) 23.

    Google Scholar 

  48. Nishio, M., Umezawa, Y., Hirota, M. and Tekeuchi, Y., Tetrahedron, 51 (1995) 8665.

    Google Scholar 

  49. Goodford, P.J., J. Med. Chem., 28 (1985) 849.

    Google Scholar 

  50. Multivariate Infometric Analysis, Perugia, Italy.

  51. Mitchell, T.J., Technometrics, 16 (1974) 203.

    Google Scholar 

  52. Steinberg, D.M. and Hunter, W.G., Technometrics, 26 (1984) 71.

    Google Scholar 

  53. Kubinyi, H., Folkers, C. and Martin, Y.C. (Eds), 3D QSAR in Drug Design, Recent Advances, Kluwer/ESCOM, Dordrecht, The Netherlands, 1998.

    Google Scholar 

  54. Pastor, M., Cruciani, G. and Clementi, S., J. Med. Chem., 40 (1997) 1455.

    Google Scholar 

  55. Baroni, M., Costantino, G., Cruciani, G., Riganelli, D., Valigi, R. and Clementi, S., Quant. Struct.-Act. Relat., 12 (1993) 9.

    Google Scholar 

  56. Dunn, D.J., Wold, S., Edlund, U. and Helberg, S., Quant. Struct.-Act. Relat., 3 (1984) 131.

    Google Scholar 

  57. Cramer, R.D., Bunce, J.D. and Patterson, D.E., Quant. Struct.-Act. Relat., 7 (1988) 18.

    Google Scholar 

  58. Kabsch, W. and Sander, C., Biopolymers, 22 (1983) 2577.

    Google Scholar 

  59. Herbert, R. and Evans, J., FEBS Lett., 385 (1996) 81.

    Google Scholar 

  60. Mannold, R., Kubinyi, H. and Timmerman, H. (Eds) Molecular Modelling-Basic Principles and Applications, VCH Publisher, Inc., New York, NY, 1996.

    Google Scholar 

  61. SPARTAN 3.0, Wave function, Inc., Irvine, USA.

  62. Farges, R., Joseph-Liauzun, E., Shire, D., Caput, D., Le Fur, G. and Ferrara, P., Mol. Pharmacol., 46 (1994) 1160.

    Google Scholar 

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Authors and Affiliations

  1. Dipartimento Farmaco Chimico, Università degli Studi di Bari, via E. Orabona 4, I-70125 , Bari, Italy

    Nunzia Cinone & Angelo Carotti

  2. Institute of Pharmaceutical Chemistry, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 1, D-40225, Düsseldorf, Germany

    Hans-Dieter Höltje

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  1. Nunzia Cinone
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  2. Hans-Dieter Höltje
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Cinone, N., Höltje, HD. & Carotti, A. Development of a unique 3D interaction model of endogenous and synthetic peripheral benzodiazepine receptor ligands. J Comput Aided Mol Des 14, 753–768 (2000). https://doi.org/10.1023/A:1008168127539

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