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Journal of Computer-Aided Molecular Design

, Volume 17, Issue 12, pp 849–859 | Cite as

Prediction of in vitro metabolic stability of calcitriol analogs by QSAR

  • Berith F. Jensen
  • Morten D. Sørensen
  • Anne-Marie Kissmeyer
  • Fredrik Björkling
  • Kim Sonne
  • Søren B. Engelsen
  • Lars Nørgaard
Article

Abstract

The metabolic stability of a drug is an important property for potential drug candidates. Measuring this property, however, can be costly and time-consuming. The use of quantitative structure-activity relationships (QSAR) to estimate the in vitro stability is an attractive alternative to experimental measurements. A data set of 130 calcitriol analogs with known values of in vitro metabolic stability was used to develop QSAR models. The analogs were encoded with molecular structure descriptors computed mainly with the commercial software QikProp and DiverseSolutions. Variable selection was carried out by five different variable selection techniques and Partial Least Squares Regression (PLS) models were generated from the 130 analogs. The models were used for prediction of the metabolic stability of 244 virtual calcitriol analogs. Twenty of the 244 analogs were selected and the in vitro metabolic stability was determined experimentally. The PLS models were able to predict the correct metabolic stability for 17 of the 20 selected analogs, corresponding to a prediction performance of 85%. The results clearly demonstrate the utility of QSAR models in predicting the in vitro metabolic stability of calcitriol analogs.

calcitriol analogs metabolic stability Partial Least Squares Regression (PLS) Quantitative Structure-Activity Relationships (QSAR) QikProp BCUTdescriptors variable selection 

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References

  1. 1.
    Abe, E., Miyaura, C. and Sakagami, H., Proc. Natl. Acad. Sci. USA,78 (1981)4990.PubMedGoogle Scholar
  2. 2.
    Kuribayashi, T., Tanaka, K., Abe, E. and Suda, T., Endocrinology, 113 (1983)1992.PubMedGoogle Scholar
  3. 3.
    Bhalla, A.K., Clemens, T., Amento, E., Holick, M.F. and Krane, S.M., J. Clin. Endocr. Metab.,57 (1983)1308.PubMedGoogle Scholar
  4. 4.
    Stumpf, W.E., Clark, S.A., Sar, M. and DeLuca, H.F., Cell Tissue Res.,238 (1984)489.CrossRefPubMedGoogle Scholar
  5. 5.
    Provvedini, D.M., Tsoukas, C.D., Deftos, L.J. and Manolagas, S.C., J. Immunol.,136 (1986)2734. J5264304.tex; 19/12/2003; 8:04; p.10.PubMedGoogle Scholar
  6. 6.
    Reichrath, J. and Holick, M.F., In Holick, M.F. (Ed.), Vitamin D: Physiology, Molecular Biology, and Clinical Applications, Vol. 1. Humana Press Inc., Totowa, NJ,1999, pp. 357–374.Google Scholar
  7. 7.
    Holick, M.F. In Holick, M.F. (Ed.), Vitamin D: Physiology, Molecular Biology, and Clinical Applications, Vol. 1. Humana Press Inc., Totowa, NJ, 1999, pp. 207–216.Google Scholar
  8. 8.
    Holick, M.F. In Holick, M.F. (Ed.), Vitamin D: Physiology, Molecular Biology, and Clinical Applications, Vol. 1. Humana Press Inc., Totowa, NJ,1999, pp. 1–16.Google Scholar
  9. 9.
    van den Bemd, G.J.C.M. and Chang, G.T.G., Curr. Drug Targets, 3 (2002)85.CrossRefPubMedGoogle Scholar
  10. 10.
    Venkatesh, S. and Lipper, R.A., J. Pharm. Sci.,89 (2000)145.CrossRefPubMedGoogle Scholar
  11. 11.
    Thompson, T.N., Med. Res. Rev.,21 (2001)412.CrossRefPubMedGoogle Scholar
  12. 12.
    Ekins, S., Waller, C.L., Swann, P.W., Cruciani, G., Wrighton, S.A. and Wikel, J.H., J. Pharmacol. Toxicol.,44 (2000)251.CrossRefGoogle Scholar
  13. 13.
    Boobis, A., Gundert-Remy, U., Kremers, P., Macheras, P. and Pelkonen, O., Eur. J. Pharm. Sci.,17 (2002)183.CrossRefPubMedGoogle Scholar
  14. 14.
    Hansch, C. and Fujita, T., J. Am. Chem. Soc.,86 (1964)1616.CrossRefGoogle Scholar
  15. 15.
    Wold, S., Martens, H. and Wold, H., In Kågström, B. and Ruhe, A., (Eds.), Lecture Notes in Mathematics Vol.973. Springer-Verlag, Berlin,1983, pp. 286–293.Google Scholar
  16. 16.
    Kissmeyer, A.-M. and Mortensen, J.T., Xenobiotica,30 (2000)815.CrossRefPubMedGoogle Scholar
  17. 17.
    Kissmeyer, A.-M., Mathiasen, I.S., Latini, S. and Binderup, L., Endocrine, 3 (1995)263.Google Scholar
  18. 18.
    Kissmeyer, A.-M., Preclinical pharmacokinetics and metabolism of EB1089 and other vitamin D analogs, Leo Pharmaceutical Products Ltd, Denmark,2000.Google Scholar
  19. 19.
    Burden, F.R., J. Chem. Inf. Comput. Sci.,29 (1989)225.CrossRefGoogle Scholar
  20. 20.
    Pearlman, R.S. and Smith, K.M., Perspect. Drug Discov. Des., 9/10/11 (1998)339.Google Scholar
  21. 21.
    Ponder, J.W. and Richards, F.M., J. Comput. Chem., 8 (1987) 1016.CrossRefGoogle Scholar
  22. 22.
    Halgren, T.A., J. Comput. Chem.,20 (1999)720.CrossRefGoogle Scholar
  23. 23.
    Halgren, T.A., J. Comput. Chem.,20 (1999)730.CrossRefGoogle Scholar
  24. 24.
    Qiu, D., Shenkin, P.S., Hollinger, F.P., Still W.C., J. Phys. Chem. A,101 (1997)3005.CrossRefGoogle Scholar
  25. 25.
    Stewart, J.J.P., J. Comput. Chem.,10 (1989)209.CrossRefGoogle Scholar
  26. 26.
    Sutter, J.M. and Kalivas, J.H., Microchem. J.,47 (1993)60.CrossRefGoogle Scholar
  27. 27.
    Nørgaard, L., Saudland, A., Wagner, J., Nielsen, J.P., Munck, L. and Engelsen, S.B., Appl. Spectrosc.,54 (2000)413.CrossRefGoogle Scholar
  28. 28.
    Höskuldsson, A., Chemometr. Intell. Lab.,23 (1994) 1.CrossRefGoogle Scholar
  29. 29.
    Baroni, M., Clementi, S., Cruciani, G., Costantino, G. and Riganelli, D., J. Chemometr., 6 (1992)347.CrossRefGoogle Scholar
  30. 30.
    Baroni, M., Costantino, G., Cruciani, G., Riganelli, D., Valigi, R. and Clementi, S., Quant. Struct.-Act. Rel.,12 (1993) 9.Google Scholar
  31. 31.
    Holland J.H. (Ed.) Adaption in Natural and Artificial Systems. University of Michigan Press, Am Arbor, Michigan,1975.Google Scholar
  32. 32.
    Martens, H. and Martens, M., Food Qual. Prefer.,11 (2000) 5.CrossRefGoogle Scholar
  33. 33.
    Wold, S., Technometrics,20 (1978)397.Google Scholar
  34. 34.
    Haaland, D.M. and Thomas, E.V., Anal. Chem.,60 (1988) 1193.CrossRefGoogle Scholar
  35. 35.
    Calverly, M.J., Binderup, E. and Binderup, L. In Norman, A.W., Bouillon, R. and Thomasset, M., (Eds.), Proceedings on the Eighth Workshop on Vitamin D, Paris, France, 5–10 July 1991, Vol. 1. Walter de Gruyter, New York,1991, pp. 163–166.Google Scholar
  36. 36.
    Dilworth, F.J., Calverley, M.J., Kakin, H.L.J. and Jones, G., Biochem. Pharmacol.,47 (1994)987.CrossRefPubMedGoogle Scholar
  37. 37.
    Jones, G. In Holick, M.F., (Ed.), Vitamin D: Physiology, Molecular Biology, and Clinical Applications, Vol. 1. Humana Press Inc., Totowa, NJ,1999, pp. 57–84.Google Scholar
  38. 38.
    Wessel, M.D., Jurs, P.C., Tolan, J.W. and Muskal, S.M., J. Chem. Inf. Comput. Sci.,38 (1998)726.CrossRefPubMedGoogle Scholar
  39. 39.
    Yoshida, F. and Topliss, J.G., J. Med. Chem., 43 (2000) 2575.CrossRefPubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Berith F. Jensen
    • 1
  • Morten D. Sørensen
    • 2
  • Anne-Marie Kissmeyer
    • 2
  • Fredrik Björkling
    • 2
  • Kim Sonne
    • 2
  • Søren B. Engelsen
    • 1
  • Lars Nørgaard
    • 1
  1. 1.Centre for Advanced Food Studies, Food Technology, Department of Dairy and Food ScienceThe Royal Veterinary and Agricultural UniversityFrederiksberg CDenmark
  2. 2.LEO Pharma A/SBallerupDenmark

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