Journal of Computer-Aided Molecular Design

, Volume 21, Issue 8, pp 437–453 | Cite as

Generation of a homology model of the human histamine H3 receptor for ligand docking and pharmacophore-based screening

  • Birgit Schlegel
  • Christian Laggner
  • Rene Meier
  • Thierry Langer
  • David Schnell
  • Roland Seifert
  • Holger Stark
  • Hans-Dieter Höltje
  • Wolfgang Sippl


The human histamine H3 receptor (hH3R) is a G-protein coupled receptor (GPCR), which modulates the release of various neurotransmitters in the central and peripheral nervous system and therefore is a potential target in the therapy of numerous diseases. Although ligands addressing this receptor are already known, the discovery of alternative lead structures represents an important goal in drug design. The goal of this work was to study the hH3R and its antagonists by means of molecular modelling tools. For this purpose, a strategy was pursued in which a homology model of the hH3R based on the crystal structure of bovine rhodopsin was generated and refined by molecular dynamics simulations in a dipalmitoylphosphatidylcholine (DPPC)/water membrane mimic before the resulting binding pocket was used for high-throughput docking using the program GOLD. Alternatively, a pharmacophore-based procedure was carried out where the alleged bioactive conformations of three different potent hH3R antagonists were used as templates for the generation of pharmacophore models. A pharmacophore-based screening was then carried out using the program Catalyst. Based upon a database of 418 validated hH3R antagonists both strategies could be validated in respect of their performance. Seven hits obtained during this screening procedure were commercially purchased, and experimentally tested in a [3H]Nα-methylhistamine binding assay. The compounds tested showed affinities at hH3R with K i values ranging from 0.079 to 6.3 μM.


Histamine H3 receptor Docking Molecular dynamics GOLD Catalyst Pharmacophore Rhodopsin 


  1. 1.
    Arrang JM, Garbarg M, Schwartz JC (1983) Nature 302:832CrossRefGoogle Scholar
  2. 2.
    Leurs R, Bakker RA, Timmerman H, De Esch IJ (2005) Nature 4:107Google Scholar
  3. 3.
    Bakker RA (2004) Inflamm Res 53:509CrossRefGoogle Scholar
  4. 4.
    Hancock AA, Esbenshade TA, Krueger KM, Yao BB (2003) Life Sci 79:3043CrossRefGoogle Scholar
  5. 5.
    Cowart M, Altenbach R, Black L, Faghih R, Zhao C, Hancock AA (2004) Mini Rev Med Chem 4:979Google Scholar
  6. 6.
    Stark H, Kathmann M, Schlicker E, Schunack W, Schlegel B, Sippl W (2004) Mini Rev Med Chem 4:965Google Scholar
  7. 7.
    De Esch IJ, Belzar KJ (2004) Mini Rev Med Chem 4:955Google Scholar
  8. 8.
    McLeod RL, Rizzo CA, West Jr RE, Aslanian R, McCormick K, Bryant M, Hsieh Y, Korfmacher W, Mingo GG, Varty L, Williams SM, Shih NY, Egan RW, Hey JA (2003) J Pharmacol Exp Ther 305:1037CrossRefGoogle Scholar
  9. 9.
    Krause M, Stark H, Schunack W (2001) Curr Med Chem 8:1329Google Scholar
  10. 10.
    Meier G, Apelt J, Reichert U, Graßmann S, Ligneau X, Elz S, Leurquin F, Ganellin CR, Schwartz JC, Schunack W, Stark H (2001) Eur J Pharm Sci 13:249CrossRefGoogle Scholar
  11. 11.
    Evers A, Klebe G (2004) J Med Chem 47:5381CrossRefGoogle Scholar
  12. 12.
    Evers A, Hessler G, Matter H, Klabunde T (2005) J Med Chem 48:5448CrossRefGoogle Scholar
  13. 13.
    Bissantz C, Bernard P, Hibert M, Rognan D (2003) Proteins 50:5CrossRefGoogle Scholar
  14. 14.
    Byvatov E, Sasse BC, Stark H, Schneider G (2005) ChemBioChem 6:997CrossRefGoogle Scholar
  15. 15.
    Becker OM, Marantz Y, Shacham S, Inbal B, Heifetz A, Kalid O, Bar-Haim S, Warshaviak D, Fichman M, Noiman S (2004) Proc Natl Acad Sci USA 101:11304CrossRefGoogle Scholar
  16. 16.
    De Esch IJ, Timmerman H, Menge WM, Nederkoorn PH (2000) Arch Pharm Pharm Med Chem 333:254CrossRefGoogle Scholar
  17. 17.
    De Esch IJ, Mills JE, Perkins TD, Romeo G, Hoffmann M, Wieland K, Leurs R, Menge WM, Nederkoorn PH, Dean P, Timmerman H (2001) J Med Chem 44:1666CrossRefGoogle Scholar
  18. 18.
    Stark H, Sippl W, Ligneau X, Arrang JM, Ganellin CR, Schwartz JC, Schunack W (2001) Bioorg Med Chem Lett 11:951CrossRefGoogle Scholar
  19. 19.
    Ligneau X, Morisset S, Tardivel-Lacombe J, Gbahou F, Ganellin CR, Stark H, Schunack W, Schwartz JC, Arrang JM (2000) Br J Pharmacol 131:1247CrossRefGoogle Scholar
  20. 20.
    Lovenberg TW, Pyati J, Chang H, Wilson SJ, Erlander MG (2000) J Pharmacol Exp Ther 293:771Google Scholar
  21. 21.
    Ballesteros JA, Weinstein H (1995) Methods Neurosci 25:366CrossRefGoogle Scholar
  22. 22.
    Uveges AJ, Kowal D, Zhang Y, Spangler TB, Dunlop J, Semus S, Jones PG (2002) J Pharmacol Exp Ther 301:451CrossRefGoogle Scholar
  23. 23.
    Jacobsen ML, Rimvall K, Hastrup S, Pettersson IV, Wulff BS (2003). Poster presentation: XXXII Annual Meeting of the European Histamine Research Society, Noordwijkerhout, NetherlandsGoogle Scholar
  24. 24.
    Yao BB, Hutchins CW, Carr TL, Cassar S, Masters JN, Bennani YL, Esbenshade TA, Hancock AA (2003) Neuropharmacology 44:773CrossRefGoogle Scholar
  25. 25.
    Fahmy K, Jäger F, Beck M, Zvyaga TA, Sakmar TP, Siebert F (1993) PNAS 90:10206CrossRefGoogle Scholar
  26. 26.
    Okada T, Fujiyoshi Y, Silow M, Navarro J, Landau EM, Shichida Y (2002) PNAS 99:5982CrossRefGoogle Scholar
  27. 27.
    Lorenzi S, Mor M, Bordi F, Rivara S, Rivara M, Moroni G, Bertoni S, Ballabeni V, Barocelli E, Placi PV (2005) Bioorg Med Chem 13:5647Google Scholar
  28. 28.
    Axe FU, Bembenek SD, Szalma S (2006) J Mol Graph Mod 24:456CrossRefGoogle Scholar
  29. 29.
    Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Science 289:739CrossRefGoogle Scholar
  30. 30.
    Canutescu AA, Shelenkov AA, Dunbrack RL (2003) Protein Sci 12:2001CrossRefGoogle Scholar
  31. 31.
    Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267:727CrossRefGoogle Scholar
  32. 32.
    Briggs JM, Madura JD, Davis ME, Gilson MK, Antosiewicz J, Luty BA, Wade RC, Bagheri B, Ilin A, Tan RC, McCammon JA. UHBD (University of Houston Brownian Dynamics), 5th edn. University of Houston Google Scholar
  33. 33.
    van der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) J Comput Chem 26:1701CrossRefGoogle Scholar
  34. 34.
    Schuler LD, Daura X, van Gunsteren WF (2001) J Comp Chem 22:1205CrossRefGoogle Scholar
  35. 35.
    Schlegel B, Sippl W, Höltje HD (2005) J Mol Model 12:49CrossRefGoogle Scholar
  36. 36.
    Pan Y, Huang N, Cho S, MacKerell AD (2003) J Chem Inf Comput Sci 43:267CrossRefGoogle Scholar
  37. 37.
    Triballeau N, Acher F, Brabet I, Pin JP, Bertrand HO (2005) J Med Chem 48:2534CrossRefGoogle Scholar
  38. 38.
    Verdonk ML, Berdini V, Hartshorn MJ, Mooij WT, Murray CW, Taylor RD, Watson P (2001) J Chem Inf Comput Sci 44:793CrossRefGoogle Scholar
  39. 39.
    Cheng Y, Prusoff WH (1973) Biochem Pharmacol 22:3099CrossRefGoogle Scholar
  40. 40.
    Lu ZL, Saldanha JW, Hulme EC (2001) J Biol Chem 276:34098CrossRefGoogle Scholar
  41. 41.
    Heitz F, Holzwarth JA, Gies JP, Pruss RM, Trumpp-Kallmeyer S, Hibert MF, Guenet C (1999) Eur J Pharmacol 380:183CrossRefGoogle Scholar
  42. 42.
    Shin N, Coates E, Murgolo NJ, Morse KL, Bayne M, Strader CD, Monsma FJ (2002) Mol Pharmacol 62:38CrossRefGoogle Scholar
  43. 43.
    Wieland K, Bongers G, Yamamoto Y, Hashimoto T, Yamatodani A, Menge WM, Timmerman H, Lovenberg TW, Leurs R (2001) J Pharm Exp Ther 299:908Google Scholar
  44. 44.
    Warhurst DC, Steele JC, Adagu IS, Craig JC, and Cullander C (2003) J Antimicrob Chemother 52:188CrossRefGoogle Scholar
  45. 45.
    Apelt J, Ligneau X, Pertz HH, Arrang JM, Ganellin CR, Schwartz JC, Schunack W, Stark H (2002) JMed Chem 45:1128CrossRefGoogle Scholar
  46. 46.
    Stark H, Purand K, Ligneau X, Rouleau A, Arrang JM, Garbarg M, Schwartz JC, Schunack W (1996) J Med Chem 39:1157CrossRefGoogle Scholar
  47. 47.
    Flohil JA, Vriend G, Berendsen HJ (2002) Proteins Structure Funct Gen 48:593CrossRefGoogle Scholar
  48. 48.
    Konvicka K, Guarnieri F, Ballesteros JA, Weinstein H (1998) Biophys J 75:601CrossRefGoogle Scholar
  49. 49.
    Nickel T, Bauer U, Schlicker E, Kathmann M, Göthert M, Sasse A, Stark H, Schunack W (2001) Br J Pharmacol 132:1665CrossRefGoogle Scholar
  50. 50.
    Faghih R, Dwight W, Vasudevan A, Dinges J, Conner SE, Esbenshade TA, Bennani YL, Hancock AA (2002) Bioorg Med Chem Lett 12:3077CrossRefGoogle Scholar
  51. 51.
    Tame JR (2005) J Comput Aided Mol Des. 19:445CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Birgit Schlegel
    • 1
  • Christian Laggner
    • 2
  • Rene Meier
    • 3
  • Thierry Langer
    • 2
  • David Schnell
    • 4
  • Roland Seifert
    • 4
  • Holger Stark
    • 5
  • Hans-Dieter Höltje
    • 1
  • Wolfgang Sippl
    • 3
  1. 1.Institute of Pharmaceutical ChemistryHeinrich-Heine-Universität DüsseldorfDusseldorfGermany
  2. 2.Institute of Pharmaceutical ChemistryLeopold-Franzens-Universität InnsbruckInnsbruckAustria
  3. 3.Department of Pharmaceutical ChemistryMartin-Luther Universität Halle-WittenbergHalle/SaaleGermany
  4. 4.Department of Pharmacology and Toxicology, Institute of PharmacyUniversity of RegensburgRegensburgGermany
  5. 5.Institute of Pharmaceutical Chemistry, Biozentrum, ZAFES/CMPJohann Wolfgang Goethe-UniversitätFrankfurtGermany

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