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3D QSAR in Drug Design pp 135–157Cite as

Pseudoreceptor Modelling in Drug Design: Applications of Yak and PrGen

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Part of the book series: Three-Dimensional Quantitative Structure Activity Relationships ((QSAR,volume 3))

Conclusion

The pseudoreceptor modelling approach discussed in this chapter tries to take advantage of the receptor fitting methodologies applied in a direct drug-design scenario for property-based receptor mapping projects, indicative for indirect drug design. A major advantage of the techniques implemented in Yak and PrGen lies in the combination of an atomistic receptor model, being represented by a truncated protein-binding cleft, and a directional force field [61–63] that is capable of treating ligand-metal ion-protein interactions, frequently found to be of prime importance for the docking event in various pharmaceutically targeted receptors and enzymes. Expanding the precursor program Yak by including pharmacophore relaxation, equilibration, receptor-mediated pharmacophore alignment, correlation-coupled minimization and the options to explore ligand and receptor space by Monte Carlo simulations certainly accounts for a more realistic approach treating pharmacophore-receptor interactions by computational means. p From our experience, we strongly believe that atomistic models help to increase the apprehension of the structure-based drug-design approach by chemists, thereby facilitating the chemical realization of proposed compounds that emerged from modelling studies.

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References

  1. Kuntz, I.D., Structure-based strategies for drug design and discovery, Science, 257 (1992) 1078–1082.

    CAS  Google Scholar 

  2. Höltje, H.-D. and Folkers, G., In Mannhold, R., Kubinyi, H. and Timmerman, H. (Eds.) Methods and principles in medicinal chemistry: Vol. 5. Molecular modeling–basic principles and applications, VCH Verlagsgesellschaft, Weinheim, Germany, 1997.

    Google Scholar 

  3. Müller, G., Feriani, A., Capelli, A.M. and Tedesco, G., Multidimensional NMR for macromolecular structure determination, La Chimica e l-Industria, 77 (1995) 937–957.

    Google Scholar 

  4. Kubinyi, H. (Ed.), 3D QSAR in drug design: Theory, methods and applications, ESCOM, Leiden. The Netherlands, 1993.

    Google Scholar 

  5. van de Waterbeemd, H., Testa, B. and Folkers, G. (Eds.), Computer-assisted lead finding and optimization: Current tools for medicinal chemistry, Verlag Helvetica Chimica Acta, Basel, Switzerland, 1997.

    Google Scholar 

  6. Vedani, A., Zbinden, P. and Snyder, J.P., Pseudo-receptor modeling: A new concept for the three-dimensional construction of receptor binding sites, J. Receptor Res., 13 (1993) 163–177.

    CAS  Google Scholar 

  7. Vedani, A., Zbinden, P., Snyder, J.P. and Greenidge, P.A., Pseudoreceptor modeling: The construction of three-dimensional receptor surrogates, J. Am. Chem. Soc., I 17 (1995) 4987–4994.

    Google Scholar 

  8. Zbinden, P., Dobler, M., Folkers, G. and Vedani, A., PrGen: Pseudo-receptor Modeling using receptor-mediated ligand alignment and pharmacophore equilibration. J. Comput.-Aided Mol. Design (in press).

    Google Scholar 

  9. Murcho, A. and Murcko, M.A., Computational methods to predict free energy in ligand-receptor complexes, J. Med. Chem., 38 (1995) 4953–4967.

    Google Scholar 

  10. Frühbeis, H., Klein, R. and Wallmeier, H., Computer-assisted molecular design: An overview, Angew. Chem. Int. Ed. Engl., 26 (1987) 403–418.

    Google Scholar 

  11. Snyder, J.P. and Rao, S.N., Pseudoreceptors: A bridge between receptor fitting and receptor mapping in drug design, Chem. Design Automation News, 4 (1989) 13–15.

    Google Scholar 

  12. Snyder, J.P. and Rao, S.N., Pseudoreceptor modeling: An experiment in large scale computation, Cray Channels, 11 (1990)4–12.

    Google Scholar 

  13. Momamy, F., Pitha, R., Klimkowsky, V.J. and Venkatachalam, C.M., Drug design using a protein pseudoreceptor. In Hohne, B.A. and Pierce, T.H. (Eds.) Expert systems applications in chemistry, ACS Symp. Ser. 408, 1989, pp. 82–91.

    Google Scholar 

  14. Hong, J.-L., Namgoong, S.K., Bernardi, A. and Still, W.C., Highly selective binding of simple peptides by a C3-macrotricyclic receptor, J. Am. Chem. Soc., 113 (1990) 5111–5112.

    Google Scholar 

  15. Snyder, J.P., Rao, S.N., Koehler, K.F. and Pellicciari, R., Drug modeling at cell membrane receptors: The concept of pseudoreceptors, In Angeli, P., Gulini, U. and Quaglia, W. (Eds.) Trends in Receptor Research, Elsevier Science Publishers, Amsterdam, The Netherlands, 1992, pp. 367–403.

    Google Scholar 

  16. Snyder, J.P., Rao, S.N., Koehler, K.F. and Vedani, A., Minireceptors and pseudoreceptors, In Kubinyi, H. (Ed.), 3D QSAR in drug design: Theory, methods and applications, ESCOM, Leiden, The Netherlands, 1993, pp. 336–354.

    Google Scholar 

  17. Höltje, H.-D. and Anzali, S., Molecular modeling studies on the digitalis binding site of the Na+/K+-ATPase, Pharmazie, 47 (1992) 691–698.

    Google Scholar 

  18. Walters, D.E. and Hinds, R.M., Genetically evolved receptor models: A computational approach to construction of receptor models, J. Med. Chem., 37 (1994) 2527–2536.

    Article  CAS  Google Scholar 

  19. Doweyko, A.M., Three-dimensional pharmacophores from binding data, J. Med. Chem., 37 (1994), 1769–1778.

    Article  CAS  Google Scholar 

  20. Hahn, M., Receptor surface models: 1. Definition and construction, J. Med. Chem., 38 (1995) 2080–2090.

    CAS  Google Scholar 

  21. Hahn, M. and Rogers, D., Receptor surface models: 2. Application to quantitative structure-activity studies, J. Med. Chem., 38 (1995) 2091–2102.

    CAS  Google Scholar 

  22. Murray-Rust, P. and Glusker, J.P., Directional hydrogen bonding to sp3-and sp3-hybridzed O atoms and its relevance to ligand-macromolecule interactions, J. Am. Chem. Soc., 106 (1984) 1018–1025.

    Article  CAS  Google Scholar 

  23. Taylor, R. and Kennard, O., Hydrogen bonding geometry in organic crystals, Acc. Chem. Res., 17 (1984) 320–326.

    Article  CAS  Google Scholar 

  24. Baker, E.N. and Hubbard, R.E., Hydrogen bonding in globular proteins, Prog. Biophys. Molec. Biol., 44 (1984) 97–179.

    Article  CAS  Google Scholar 

  25. Vedani, A. and Dunitz, J.D., Lone-pair directionality of H-bond potential functions for molecular mechanics calculations: The inhibition of human carbonic anhydrase II by sulfonamides, J. Am. Chem. Soc., 107 (1985) 7653–7658.

    Article  CAS  Google Scholar 

  26. Tintelnot, M. and Andrews, P., Geometries of functional group interactions in enzyme-ligand complexes: Guides for receptor modeling, J. Comput.-Aided Mol. Design, 3 (1989) 67–84.

    Article  CAS  Google Scholar 

  27. Alexander, R.S., Kanyo, Z.F., Chirlian, L.E. and Christianson, D.W., The stereochemistry of phosphate-lewis acid interactions for nucleic acid structure and recognition, J. Am. Soc., 112 (1990) 933–937.

    CAS  Google Scholar 

  28. Klebe, G. and Diederich, F.A., A comparison of the crystal packing in benzene with the geometry seen in crystalline cyclophane-benzene complexes: Guidelines for rational design, Phil. Trans. Roy. Soc., London, ser. A, 345 (1993) 37–48.

    CAS  Google Scholar 

  29. Klebe, G., The use of composite crystal-field environments in molecular recognition and the de novo design of protein ligands, J. Mol. Biol., 237 (1994) 212–235.

    Article  CAS  Google Scholar 

  30. Kern, P., Brunne, R.M., Rognan, D. and Folkers, G., A pseudo-particle approach for studying protein-ligand models truncated to their active site, Biopolymers, 38 (1996) 619–637.

    Article  CAS  Google Scholar 

  31. Blaney, J.M., Weiner, P.K., Dearing, A., Kollman, P.A., Jorgensen, E.C., Oatley, S.J., Burridge, J.M. and Blake, J.F., Molecular mechanics simulation of protein-ligand interactions: Binding of thyroid analogues to prealbumin, J. Am. Chem. Soc., 104 (1982) 6424–6434.

    Article  CAS  Google Scholar 

  32. Still, W.C., Tempczyk, A., Hawley, R.C. and Hendrickson, T., Semianalytical treatment of solvation of molecular mechanics and dynamics, J. Am. Chem. Soc., 112 (1990) 6127–6129.

    Article  CAS  Google Scholar 

  33. Searle, M.S. and Williams, D.H., The cost of conformational order: Entropy changes in molecular associations, J. Am. Chem. Soc., 114 (1992) 10690–10697.

    CAS  Google Scholar 

  34. Iismaa, T.P., Biden, T.J. and Shine, J. (Eds.), G Protein-coupled receptors, Springer-Verlag, Heidelberg, Germany, 1995.

    Google Scholar 

  35. Heavner, G.A., Active sequences in cell adhesion molecules: Targets for therapeutic intervention, Drug Discovery Today, 1 (1997) 295–304.

    Google Scholar 

  36. D-Souza, S.E., Ginsberg, M.H. and Plow, E.F., Arginyl-glycyl-aspartic acid (RGD): A cell adhesion motif, Trends Biochem. Sci., 16 (1991) 246–250.

    CAS  Google Scholar 

  37. Engleman, V.W., Kellogg, M.S. and Rogers, T.E., Cell adhesion integrins as pharmaceutical targets, Annu. Rep. Med. Chem., 31 (1996) 191–200.

    CAS  Google Scholar 

  38. Gurrath, M., Müller, G., Kessler, H., Aumailley, M. and Timpl, R., Conformation/activity studies of rationally designed potent anti-adhesive RGD peptides, Eur. J. Biochem., 210 (1992) 911–921.

    Article  CAS  Google Scholar 

  39. Pfaff, M., Tangemann, K., Müller, B., Gurrath, M., Müller, G., Kessler, H., Timpl, R. and Engel, J., Selective recognition of cyclic RGD peptides of NMR defined conformation by α Nb β 3. α v β 3. and α c β l integrins, J. Biol. Chem., 296 (1994) 20233–20238.

    Google Scholar 

  40. Johnson, M.R., Melvin, L.S., Althuis, T.H., Bindra, J.S., Harbert, C.A., Milne, G.M. and Weissman, A., Selective and potent analgesics derived from cannabinoids, J. Clin. Pharmacol., 21 (1981) 271–282.

    CAS  Google Scholar 

  41. Johnson, M.R. and Melvin, L.S., The discovery of non-classical cannabinoids, In Mechoulam, R. (Ed.) Cannabinoids as therapeutic agents, CRC Press, Boca Raton, FL, 1986, pp. 121–146.

    Google Scholar 

  42. Razdan, R.K., Structure-activity relationships in cannabinoids, Pharmacol. Rev., 38 (1986) 75–149.

    CAS  Google Scholar 

  43. Main, B.G., βreceptors, In Emmett, J.C. (Ed.) Comprehensive medicinal chemistry, Volume 3. Membranes and receptors, Pergamon Press, Oxford, U.K., 1990, pp. 187–228.

    Google Scholar 

  44. Kontoyianni, M., DeWeese, C., Penzotti, J.E. and Lybrand T.P., Three-dimensional models for agonist and antagonist complexes with βadrenergic receptor, J. Med. Chem., 39 (1996) 4406–4420.

    Article  CAS  Google Scholar 

  45. Nederkoorn, P.H., van Lenthe, J.H., van der Goot, H., Donné-Op den Kelder, G.M. and Timmerman, J., The agonistic binding site at the histamine H 2 receptor: 1. Theoretical investigations of histamine binding to an oligopeptide mimicking a part of the fifth transmembrane α helix, Comput.-Aided Mol. Design, 10 (1996) 461–478.

    CAS  Google Scholar 

  46. Nederkoorn, P.H.J., van Gelder, E.M., Donné-Op den Kelder, G. and Timmerman, J., The agonistic binding site at the histamine H 2 receptor: 2. Theoretical investigations of histamine binding to receptor models of the seven α-helical transmembrane domain, Comput.-Aided Mol. Design, 10 (1996) 479–489.

    CAS  Google Scholar 

  47. Arrang, J.M., Garbarg, M. and Schwartz., J.-C., Auto-inhibition of brain histamine release by a novel class of histamine receptors, Nature, 302 (1983) 832–837.

    Article  CAS  Google Scholar 

  48. Lipp, R., Stark, H. and Schunack, W., Absolute configuration, stereochemistry and receptor selectivity of (R)α(S)β-dimethylhistamine, a novel highly potent histamine H 3 -receptor agonist. In Schwartz, J.-C. and Haas, H.L. (Eds.) The histamine receptor: Vol. 16, Wiley-Liss Inc., New York, 1992, pp. 57–72.

    Google Scholar 

  49. Shih, N.-Y., Aslanian, R., Lupo, A.T., Duguma, L., Orlando, S., Piwinski, J.J., Green, M.J., Gangluy, A.K., Clark, M., Tozzi, S., Kreutner, W. and Hey, J.A., A novel pyrrolidine analog of histamine as potent, highly selective histamine H 3 -receptor agonist, J. Med. Chem., 38 (1995) 1593–1599.

    Article  CAS  Google Scholar 

  50. Vollinga, R.C., de Koning, P., Jansen, F. P., Leurs, R., Menge, W.M.P.B. and Timmerman, H., A new potent and selective histamine H 3 -receptor agonist: 4-( 1H-imidazol-4yl-methyl)-piperidine, J. Med. Chem., 37 (1994) 332–333.

    Article  CAS  Google Scholar 

  51. Howson, W., Parson, M.E., Raval, P. and Swayne, G.T.G., Two novel potent and selective histamine H 3 -receptor agonists, Bioorg. Med. Chem. Lett., 2 (1992) 77–78.

    CAS  Google Scholar 

  52. Ganellin, C.R., Bang-Andersen, B., Khalaf, Y.S., Tertiuk, W., Arrang, J.M., Garbarg, M., Ligneau, X., Rouleau, A. and Schwartz, J.C., Imetit and N-methyl derivatives: The transition from potent agonists to antagonists at histamine H 3 -receptors, Bioorg. med. Chem. Lett., 2 (1992) 1231–1234.

    Article  CAS  Google Scholar 

  53. Sippl, W., Stark, H. and Höltje, H.-D., Computer-assisted analysis of histamine H 2 -and H 3 -receptor agonists, Quant. Struct.-Act. Relat., 1 (1995) 121–125.

    Google Scholar 

  54. Goodford, P.J., A computational procedure for determining energetically favourable binding sties on biologically important macromolecules, J. Med. Chem., 27 (1985) 849–857.

    Google Scholar 

  55. Yao, N., Trakhanow, S. and Quiocho, F.A., Refine structure of the histamine binding protein complexed with histamine and its relationship with many other active transport/chemosensory proteins, Biochemistry, 33 (1994) 4769–4775.

    CAS  Google Scholar 

  56. See e.g. Cox, D., Aoki, T., Seki, J., Motoyama, Y. and Yoshida, K., The pharmacology of the integrins, Med. Res. Rev., 14 (1994) 195–228.

    Google Scholar 

  57. Samanen, J., GPIIb/IIIa antagonists, Annu. Rep. Med. Chem., 31 (1996) 91–100.

    CAS  Google Scholar 

  58. Smith, J.W. and Cheresh, D.A., lIntegrin (α,β)-ligand interaction, J. Biol. Chem., 265 (1990) 2168–2172.

    CAS  Google Scholar 

  59. Müller, G., Gurrath, M. and Kessler, H., Pharmacophore refinement of gpIIb/IIIa antagonists based on comparative studies of antiadhesive cyclic and acyclic RGD peptides, J. Comput.-Aided Mol. Design, 8 (1994) 709–730.

    Google Scholar 

  60. Manallack, D.T., Getting that hit: 3D database searching in drug discovery, Drug Design Today, 1 (1997) 231–238.

    Google Scholar 

  61. Vedani, A., Dobler, M. and Dunitz., J.D., An empirical potential function for metal centers: Application to molecular mechanics calculations on metalloproteins, J. Comput. Chem., 7 (1986) 701–710.

    Article  CAS  Google Scholar 

  62. Vedani, A., YETI: An interactive molecular mechanics program for small-molecule protein complexes, J. Comput. Chem., 9 (1988) 269–280.

    Article  CAS  Google Scholar 

  63. Vedani, A. and Huhta, D.W., A new force field for modeling metalloproteins, J. Am. Chem. Soc., 112 (1990) 4759–4767.

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Institute for Pharmaceutical Chemistry, Heinrich Heine University-Düsseldorf, Universitätsstr. 1, D-40225, Düsseldorf, Germany

    Marion Gurrath & Hans-Dieter Höltje

  2. Bayer AG, IM-FA, Computational Chemistry, Q18, D-51368, Leverkusen, Germany

    Gerhard Müller

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  1. Marion Gurrath
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  2. Gerhard Müller
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  3. Hans-Dieter Höltje
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Editors and Affiliations

  1. ZHF/G, A30, BASF AG, D-67056, Ludwigshafen, Germany

    Hugo Kubinyi

  2. Department Pharmazie, ETH-Zürich, Winterthurer Strasse 190, CH-8057, Zürich, Switzerland

    Gerd Folkers

  3. Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL, 60064-3500, USA

    Yvonne C. Martin

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Gurrath, M., Müller, G., Höltje, HD. (1998). Pseudoreceptor Modelling in Drug Design: Applications of Yak and PrGen. In: Kubinyi, H., Folkers, G., Martin, Y.C. (eds) 3D QSAR in Drug Design. Three-Dimensional Quantitative Structure Activity Relationships, vol 3. Springer, Dordrecht. https://doi.org/10.1007/0-306-46858-1_9

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  • DOI: https://doi.org/10.1007/0-306-46858-1_9

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