Skip to main content
Log in

Relative binding orientations of adenosine A1 receptor ligands — A test case for Distributed Multipole Analysis in medicinal chemistry

  • Research Papers
  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Summary

The electrostatic properties of adenosine-based agonists and xanthine-based antagonists for the adenosine A1 receptor were used to assess various proposals for their relative orientation in the unknown binding site. The electrostatic properties were calculated from distributed multipole representations of SCF wavefunctions. A range of methods of assessing the electrostatic similarity of the ligands were used in the comparison. One of the methods, comparing the sign of the potential around the two molecules, gave inconclusive results. The other approaches, however, provided a mutually complementary and consistent picture of the electrostatic similarity and dissimilarity of the molecules in the three proposed relative orientations. This was significantly different from the results obtained previously with MOPAC AM1 point charges. In the standard model overlay, where the aromatic nitrogen atoms of both agonists and antagonists are in the same position relative to the binding site, the electrostatic potentials are so dissimilar that binding to the same receptor site is highly unlikely. Overlaying the N6-region of adenosine with that near C8 of theophylline (the N6-C8 model) produces the greatest similarity in electrostatic properties for these ligands. However, N6-cyclopentyladenosine (CPA) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) show greater electrostatic similarity when the aromatic rings are superimposed according to the flipped model, in which the xanthine ring is rotated around its horizontal axis. This difference is mainly attributed to the change in conformation of N6-substituted adenosines and could result in a different orientation for theophylline and DPCPX within the receptor binding site. However, it is more likely that DPCPX also binds according to the N6-C8 model, as this model gives the best steric overlay and would be favoured by the lipophilic forces, provided that the binding site residues could accommodate the different electrostatic properties in the N6/N7-region. Finally, we have shown that Distributed Multipole Analysis (DMA) offers a new, feasible tool for the medicinal chemist, because it provides the use of reliable electrostatic models to determine plausible relative binding orientations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

DMA:

distributed multipole analysis

SCF:

self-consistent field

CPA:

N6-cyclopentyladenosine

DPCPX:

1,3-dipropyl-8-cyclopentylxanthine

R-PIA:

R-1-phenyl-2-propyladenosine

S-PIA:

S-1-phenyl-2-propyladenosine

References

  1. Davis, A., Warrington, B.H. and Vinter, J.G., J. Comput.-Aided Mol. Design, 1 (1987) 97.

    Google Scholar 

  2. Jacobson, K.A., van Galen, P.J.M. and Williams, M., J. Med. Chem., 35 (1992) 407.

    Google Scholar 

  3. Daly, J.W., In Cooper, D.M.F. and Saemuk, K.B. (Eds.) Advances in Cyclic Nucleotide and Protein Phosphorylation Research, Vol. 19, Raven Press, New York, NY, 1985, pp. 29–45.

    Google Scholar 

  4. van der Wenden, E.M., IJzerman, A.P. and Soudijn, W., J. Med. Chem., 35 (1992) 629.

    Google Scholar 

  5. van Galen, P.J.M., van Vlijmen, H.W.Th., IJzerman, A.P. and Soudijn, W., J. Med. Chem., 33 (1990) 1708.

    Google Scholar 

  6. Peet, N.P., Lentz, N.L., Meng, E.C., Dudley, M.W., Ogden, A.M.L., Demeter, D.A., Weintraub, H.J.R. and Bey, P., J. Med. Chem., 33 (1990) 3127.

    Google Scholar 

  7. Stone, A.J. and Alderton, M., Mol. Phys., 56 (1985) 1047.

    Google Scholar 

  8. Stone, A.J., Chem. Phys. Lett., 83 (1081) 233.

    Google Scholar 

  9. van Galen, P.J.M., Leusen, F.J.J., IJzerman, A.P. and Soudijn, W., Eur. J. Pharmacol. Mol. Pharmacol., 172 (1989) 19.

    Google Scholar 

  10. van der Wenden, E.M., van Galen, P.J.M., IJzerman, A.P. and Soudijn, W., Eur. J. Pharmacol., Mol. Pharmacol. Sect., 206 (1991) 315.

    Google Scholar 

  11. Bruns, R.F., Can. J. Physiol. Pharmacol., 58 (1980) 673.

    Google Scholar 

  12. Brinkley, J.S., Pople, J.A. and Hehre, W.J., J. Am. Chem. Soc., 102 (1980) 939.

    Google Scholar 

  13. CADPAC5: The Cambridge Analytic Derivatives Package Issue 5, Cambridge, 1992. Developed by Amos, R.D., with contributions from Alberts, I.L., Andrews, J.S., Colwell, S.M., Handy, N.C., Jayatilakam, D., Knowles, P.J., Kobayasi, R., Koga, N., Laidig, K.E., Murray, C.W., Rice, J.E., Sanz, J., Simandiras, E.D., Stone, A.J. and Su, M.-D.

  14. Price, S.L., Andrews, J.S., Murray, C.W. and Amos, R.D., J. Am. Chem. Soc., 114 (1992) 8268.

    Google Scholar 

  15. Price, S.L. and Stone, A.J., J. Chem. Phys., 86 (1987) 2859.

    Google Scholar 

  16. Buckingham, A.D. and Fowler, P.W., Can. J. Chem., 63 (1985) 2018.

    Google Scholar 

  17. Price, S.L., Stone, A.J. and Alderton, M., Mol. Phys., 52 (1984) 987.

    Google Scholar 

  18. Stone, A.J., ORIENT, Version 2: A program for calculating electrostatic interactions between molecules, University of Cambridge, Cambridge, 1990.

    Google Scholar 

  19. Price, S.L. and Stone, A.J., J. Chem. Soc., Faraday Trans., 88 (1992) 1755.

    Google Scholar 

  20. Hodgkin, E.E. and Richards, W.G., Int. J. Quantum Chem., Quantum Biol. Symp., 14 (1987) 105.

    Google Scholar 

  21. Apaya, R. and Price, S.L., J. Comput.-Aided Mol. Design, submitted for publication.

  22. IJzerman, A.P., van Galen, P.J.M. and Jacobson, K.A., Drug Des. Discov., 9 (1992) 49.

    Google Scholar 

  23. Carbó, R., Leyda, L. and Arnau, M., Int. J. Quantum Chem., 17 (1980) 1185.

    Google Scholar 

  24. Burt, C. and Richards, W.G., J. Comput.-Aided Mol. Design, 4 (1990) 231.

    Google Scholar 

  25. Hermann, R.B. and Herron, D.K., J. Comput.-Aided Mol. Design, 5 (1991) 511.

    Google Scholar 

  26. Ukena, D., Padgett, W.L., Hong, O., Daly, J.W., Daly, D.T. and Olsson, R.A., FEBS Lett., 215 (1987) 203.

    Google Scholar 

  27. Klotz, K.N., Lohse, M.J. and Schwabe, U., J. Biol. Chem., 263 (1988) 17522.

    Google Scholar 

  28. Garritsen, A., IJzerman, A.P., Beukers, M.W. and Soudijn, W., Biochem. Pharmacol., 40 (1990) 835.

    Google Scholar 

  29. Olah, M.E., Ren, H., Ostrowski, J., Jacobson, K.A. and Stiles, G.L., J. Biol. Chem., 267 (1992) 10764.

    Google Scholar 

  30. Clanachan, A.S., Can. J. Physiol. Pharmacol., 59 (1981) 603.

    Google Scholar 

  31. van Galen, P.J.M., IJzerman, A.P. and Soudijn, W., Nucleosides Nucleotides, 9 (1990) 275.

    Google Scholar 

  32. Müller, C.E. and Scior, T., Pharm. Act. Helv., 68 (1993) 77.

    Google Scholar 

  33. Dewar, M.J.S., Zoebisch, E.F., Healey, E.F. and Stewart, J.J.P., J. Am. Chem. Soc., 107 (1985) 3902.

    Google Scholar 

  34. Stewart, J.J.P., J. Comput.-Aided Mol. Design, 4 (1990) 1.

    Google Scholar 

  35. Hunter, A.C., Singh, J. and Thornton, J.M., J. Mol. Biol., 218 (1991) 837.

    Google Scholar 

  36. Price, S.L. and Stone, A.J., J. Chem. Phys., 86 (1987) 2859.

    Google Scholar 

  37. The Chem-X Suite, Reference Manual, July 1988 Update, Chemical Design Ltd., Oxford.

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

van der Wenden, E.M., Price, S.L., Apaya, R.P. et al. Relative binding orientations of adenosine A1 receptor ligands — A test case for Distributed Multipole Analysis in medicinal chemistry. J Computer-Aided Mol Des 9, 44–54 (1995). https://doi.org/10.1007/BF00117277

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00117277

Keywords

Navigation