Advertisement

Journal of Molecular Modeling

, Volume 13, Issue 1, pp 121–131 | Cite as

Structure-based 3D-QSAR studies on thiazoles as 5-HT3 receptor antagonists

  • Li-Ping Zhu
  • De-Yong Ye
  • Yun Tang
Original Paper

Abstract

Structure-based 3D-QSAR studies were performed on 20 thiazoles against their binding affinities to the 5-HT3 receptor with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The thiazoles were initially docked into the binding pocket of a human 5-HT3A receptor homology model, constructed on the basis of the crystal structure of the snail acetylcholine binding protein (AChBP), using the GOLD program. The docked conformations were then extracted and used to build the 3D-QSAR models, with cross-validated \( r^{2}_{{cv}} \) values 0.785 and 0.744 for CoMFA and CoMSIA, respectively. An additional five molecules were used to validate the models further, giving satisfactory predictive \( r^{2} \) values of 0.582 and 0.804 for CoMFA and CoMSIA, respectively. The results would be helpful for the discovery of new potent and selective 5-HT3 receptor antagonists.

Keywords

Structure-based 3D-QSAR CoMFA CoMSIA 5-HT3 receptor antagonists Homology modeling 

References

  1. 1.
    Wolf H (2000) Scand J Rheumatol 29:37–45CrossRefGoogle Scholar
  2. 2.
    Haus U, Spath M, Farber L (2004) Scand J Rheumatol 33:12–18CrossRefGoogle Scholar
  3. 3.
    Karim F, Roerig SC, Saphier D (1996) Biochem Pharmacol 52:685–692CrossRefGoogle Scholar
  4. 4.
    Israili ZH (2001) Curr Med Chem—Central Nervous System Agents 1:171–199CrossRefGoogle Scholar
  5. 5.
    Lummis SCR, Reeves DC (2002) Mol Membrane Biol 19:11–26CrossRefGoogle Scholar
  6. 6.
    Boess FG, Beroukhim R, Martin IL (1995) J Neurochem 64:1401–1405CrossRefGoogle Scholar
  7. 7.
    Boess FG, Steward LJ, Steele JA, Liu D, Reid J, Glencorse TA, Martin IL (1997) Neuropharmacol 36:637–647CrossRefGoogle Scholar
  8. 8.
    Brejc K, Van Dijk WJ, Klaassen RV, Schuurmans M, van der Oost J, Smit AB, Sixma TK (2001) Nature 411:269–276CrossRefGoogle Scholar
  9. 9.
    Maksay G, Bikádi Z, Simonyi MJ (2003) Recept Signal Transduct Res 23:255–270CrossRefGoogle Scholar
  10. 10.
    Cramer III RD, Patterson DE, Bunce JD (1998) J Am Chem Soc 110:5959–5967CrossRefGoogle Scholar
  11. 11.
    Klebe G, Abraham U, Mietzner T (1994) J Med Chem 37:4130–4146CrossRefGoogle Scholar
  12. 12.
    Rosen T, Nagel AA, Rizzi JP, Ives JL, Daffeh JB, Ganong AH, Guarino K, Heym J, McLean S, Nowakowski JT, Schmidt AW, Seeger TF, Siok CJ, Vincent LA (1990) J Med Chem 33:2715–2720CrossRefGoogle Scholar
  13. 13.
    Nagel AA, Rosen T, Rizzi J, Daffeh J, Guarino K, Nowakowski J, Vincent LA, Heym J, McLean S, Seeger T, Connolly M, Schmidt AW, Siok C (1990) J Med Chem 33:13–16CrossRefGoogle Scholar
  14. 14.
    SYBYL, version 6.9. (2004) Molecular Modeling Software, Tripos Associates Inc, 1669, South Hanley Road, Suite 303, St. Louis, Missouri, MO 63144–2913, USAGoogle Scholar
  15. 15.
    Pearlman DA, Case DA, Kollman PA (2004) AMBER 4.1. University of California, San Francisco, CAGoogle Scholar
  16. 16.
    Laskowski RA (1993) J Appl Cryst 26:283–291CrossRefGoogle Scholar
  17. 17.
    GOLD, version 2.2. (2004) CCDC Software Ltd, 12 Union Road, Cambridge CB2 1EZ, United Kingdom, http://www.ccdc.cam.ac.uk
  18. 18.
    Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) J Mol Biol 267:727–748CrossRefGoogle Scholar
  19. 19.
    Jones G, Willett P, Glen RC (1995) J Mol Biol 245:43–53CrossRefGoogle Scholar
  20. 20.
    Wold S, Ruhe A, Wold H, Dunn III WJ (1984) SIAM J Sci Stat Comput 5:735–743CrossRefGoogle Scholar
  21. 21.
    Cramer III RD, Bunce JD, Patterson DE (1988) Quant Struct-Act Relat 7:18–25CrossRefGoogle Scholar
  22. 22.
    Bush BL, Nachbar Jr RB (1993) J Comput-Aided Mol Des 7:587–619CrossRefGoogle Scholar
  23. 23.
    Hibert MF, Hoffmann R, Miller RC, Carr AA (1990) J Med Chem 33:1594–1600CrossRefGoogle Scholar
  24. 24.
    Thompson AJ, Price KL, Reeves DC, Chan SL, Chau PL, Lummis SCR (2005) J Biol Chem 280:20476–20482CrossRefGoogle Scholar
  25. 25.
    Pontius J, Richelle J, Wodak SJ (1996) J Mol Biol 264:121–136CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Department of Medicinal ChemistrySchool of Pharmacy, Fudan UniversityShanghaiChina
  2. 2.School of Pharmacy, East China University of Science and TechnologyShanghaiChina

Personalised recommendations