Journal of Computer-Aided Molecular Design

, Volume 19, Issue 8, pp 617–623 | Cite as

VolSurf analysis of pharmacokinetic properties for several antifungal sesquiterpene lactones isolated from Greek Centaurea sp.

  • Catherine Koukoulitsa
  • George D. Geromichalos
  • Helen Skaltsa
Article

Summary

Sesquiterpene lactones are terpenoid compounds characteristic of the Asteraceae (Compositae) possessing a variety of biological activities, such as cytotoxic, antitumor, antibacterial, and antifungal. The prediction of the pharmacokinetic profile of several antifungal sesquiterpene lactones, isolated from Greek taxa of Centaurea sp., was undertaken in this study using the VolSurf procedure. The molecules were projected on the following pre-calculated ADME models: Caco-2 cell permeability, plasma protein affinity, blood–brain barrier permeation and thermodynamic solubility. The in silico projection revealed a non optimal pharmacokinetic profile for the studied compounds. ADME in silico screening of a semi-synthetic derivatives virtual library has been performed in order to optimize the pharmacokinetic properties. A number of derivatives were proposed as it was predicted to have higher Caco-2 cell permeability, while the pharmacokinetic behaviour regarding BBB penetration, protein binding and solubility was mainly preserved.

Keywords

ADME, sesquiterpene lactones, virtual screening, VolSurf 

Abbreviations

ADME

absorption, distribution, metabolism, excretion

BBB

blood brain barrier

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgements

We are grateful to Prof. Gabriele Cruciani (Laboratory for Chemometrics, School of Chemistry, University of Perugia, Italy) for providing us the VolSurf program (version 4, Linux, www.moldiscovery.com), and also to Dr. Emanuele Carosati and Dr. Giovanni Cianchetta (same laboratory) for helpful advises. This research was financially supported by the Italian Ministry of Education.

References

  1. 1.
    Bindseil K.U., Jakupovic J., Wolf D., Lavayre J., Leboul J., van der Pyl D., (2001) Drug Discov. Today 6: 840CrossRefGoogle Scholar
  2. 2.
    Lee M.L., Schneider G., (2001) J. Comb. Chem. 3: 284CrossRefGoogle Scholar
  3. 3.
    Walters W.P., Stahl M.T., Murcko M.A., (1998) Drug Discov. Today 3: 160CrossRefGoogle Scholar
  4. 4.
    Golebiowski A., Klophenstein S.R., Portlock D.E., (2001) Curr. Opin. Chem. Biol., 5: 273CrossRefGoogle Scholar
  5. 5.
    Lyne P.D., (2002) Drug Discov. Today 7: 1047CrossRefGoogle Scholar
  6. 6.
    Green D.V.S., (2003) Prog. Med. Chem. 41: 61CrossRefGoogle Scholar
  7. 7.
    Lipinski C.A., Lombardo F., Dominy B.W., Feeney P.J., (1997) Adv. Drug delivery Rev. 23: 3CrossRefGoogle Scholar
  8. 8.
    Ekins S., Waller C.L., Swaan P.W., Cruciani G., Wrighton S.A., Wikel J.H., (2000) J. Pharmacol. Toxicol. Methods 44: 251CrossRefGoogle Scholar
  9. 9.
    Van de Waterbeemd H., Camenisch G., Folkers G.,. Raevsky O.A, (1996) Quant. Struct.-Act. Relat. 15: 480CrossRefGoogle Scholar
  10. 10.
    Cruciani G., Pastor M., Guba W., (2000) European J. Pharm. Sci. 11(Suppl. 2): S29CrossRefGoogle Scholar
  11. 11.
    Goodford P.J., (1985) J. Med. Chem. 28: 849CrossRefGoogle Scholar
  12. 12.
    Cruciani, G., Crivori, P., Carrupt, P.-A. and Testa B., J.␣Mol. Str.: Theochem, 503 (2000) 17Google Scholar
  13. 13.
    Crivori P., Cruciani G., Carrupt P.-A., Testa B., (2000) J. Med. Chem. 43: 2204CrossRefGoogle Scholar
  14. 14.
    Cruciani, G., Meniconi, M., Carosati, E., Zamora, I. and Mannhold, R., In Waterbeemd, H., Lennernäs, H. and Artursson, P. (Eds.), VOLSURF: A Tool for Drug ADME-properties Prediction, WILEY-VCH, Weinheim, Germany, 2003, pp. 406–419Google Scholar
  15. 15.
    Crivori P., Zamora I., Speed B., Orrenius C., Poggesi I., (2004) J. Comput.-Aid. Mol. Des., 18: 155CrossRefGoogle Scholar
  16. 16.
    Skaltsa H., Lazari D., Garcia B., Pedro J.R., Sokovic M., Constantinidis T., (2000) Z. Naturforsch. C 55c: 534Google Scholar
  17. 17.
    Skaltsa H., Lazari D., Panagouleas C., Georgiadou E., Garcia B., Sokovic M., (2000) Phytochemistry 55: 903CrossRefGoogle Scholar
  18. 18.
    Karioti A., Skaltsa H., Lazari D., Sokovic M., Garcia B., Harvala C., (2002) Z. Naturforsch. C 57c: 75Google Scholar
  19. 19.
    Sybyl Molecular Modeling System, version 6. 8. 1; Tripos Assoc.: St. Louis, MOGoogle Scholar
  20. 20.
    Vinter J.G., Davis A., Saunders M.R., (1987) J. Comput.-Aided Mol. Des. 1: 31CrossRefGoogle Scholar
  21. 21.
    Rodriguez E., Towers G.H.N., Mitchell J.C.. (1976) Phytochemistry 15: 1573CrossRefGoogle Scholar
  22. 22.
    Fischer, N.H., Olivier, E.J. and Fischer, H.D., In Hertz, W., Grisebach, H., Kirby, G.W. (Eds.), Progress in the Chemistry of Organic Natural Products. Springer-Verlag, Wien, New York, 1979, pp. 47–390Google Scholar
  23. 23.
    Seaman F.C., (1982) Bot. Rev. 48: 121Google Scholar
  24. 24.
    Picman A.K., (1986) Biochem. Syst. Ecol. 14: 255CrossRefGoogle Scholar
  25. 25.
    Robles M., Aregullin M., West J., Rodriguez E., (1995) Planta Med. 61: 199Google Scholar
  26. 26.
    Wedge, D.E., Galindo, J.C.G. and Macías, F.A., Phytochemistry, 53 (2000) 747Google Scholar
  27. 27.
    Vajs V., Todorović N., Ristić M., Tešević V., Todorović B., Janaćković P., Marin P., Milosaljević S., (1999) Phytochemistry 52: 383CrossRefGoogle Scholar
  28. 28.
    Barrero A.F., Oltra J.E., Alvarez M., Raslan D.S., Saude D.A., Akssira M., (2000) Fitoterapia 71: 60CrossRefGoogle Scholar
  29. 29.
    Kupchan S.M., Fessler D.C., Eakin M.A., Giacobbe T.J., (1970) Science 168: 376CrossRefGoogle Scholar
  30. 30.
    Hanson R.L., Lardy H.A., Kupchan S.M., (1970) Science 168: 378CrossRefGoogle Scholar
  31. 31.
    Smith C.H., Larner J., Thomas A.M., Kupchan S.M., (1972) Biochim. Biophys. Acta 276: 94Google Scholar
  32. 32.
    Picman A.K., (1984) Biochem. Syst. Ecol. 12: 13CrossRefGoogle Scholar
  33. 33.
    Inoue A., Tamogami S., Kato H., Nakazato Y., Akiyama M., Kodama O., Akatsuka T., Hashidoko Y., (1995) Phytochemistry 39: 845CrossRefGoogle Scholar
  34. 34.
    Oprea T., (2002) Molecules 7: 51Google Scholar
  35. 35.
    Zamora I., Oprea T., Cruciani G., Pastor M., Ungell A.-L., (2003) J. Med. Chem., 46: 25CrossRefGoogle Scholar
  36. 36.
    Koukoulitsa, E., Skaltsa, H., Demetzos, C. and Cruciani, G., 11th Panhellenic Pharmaceutical Congress, Athens, Greece Special Issue of Eur. J. Drug Metabol. Pharmacokinet., 28 (2003) 7Google Scholar
  37. 37.
    Koukoulitsa, C., Skaltsa, H. and Cruciani, G., 15th European Symposium on Quantitative Structure-Activity Relationships & Molecular Modelling, Istanbul, Turkey, September 05–10, 2004, proceedings in pressGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Catherine Koukoulitsa
    • 1
  • George D. Geromichalos
    • 2
  • Helen Skaltsa
    • 1
  1. 1.Department of Pharmacognosy & Chemistry of Natural Products, School of PharmacyUniversity of AthensAthensGreece
  2. 2.Symeonidio Research CenterTheagenio Cancer HospitalThessalonikiGreece

Personalised recommendations