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Prediction of in vitro metabolic stability of calcitriol analogs by QSAR

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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.

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References

  1. Abe, E., Miyaura, C. and Sakagami, H., Proc. Natl. Acad. Sci. USA,78 (1981)4990.

    PubMed  Google Scholar 

  2. Kuribayashi, T., Tanaka, K., Abe, E. and Suda, T., Endocrinology, 113 (1983)1992.

    PubMed  Google Scholar 

  3. Bhalla, A.K., Clemens, T., Amento, E., Holick, M.F. and Krane, S.M., J. Clin. Endocr. Metab.,57 (1983)1308.

    PubMed  Google Scholar 

  4. Stumpf, W.E., Clark, S.A., Sar, M. and DeLuca, H.F., Cell Tissue Res.,238 (1984)489.

    Article  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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. 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. 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. van den Bemd, G.J.C.M. and Chang, G.T.G., Curr. Drug Targets, 3 (2002)85.

    Article  PubMed  Google Scholar 

  10. Venkatesh, S. and Lipper, R.A., J. Pharm. Sci.,89 (2000)145.

    Article  PubMed  Google Scholar 

  11. Thompson, T.N., Med. Res. Rev.,21 (2001)412.

    Article  PubMed  Google Scholar 

  12. Ekins, S., Waller, C.L., Swann, P.W., Cruciani, G., Wrighton, S.A. and Wikel, J.H., J. Pharmacol. Toxicol.,44 (2000)251.

    Article  Google Scholar 

  13. Boobis, A., Gundert-Remy, U., Kremers, P., Macheras, P. and Pelkonen, O., Eur. J. Pharm. Sci.,17 (2002)183.

    Article  PubMed  Google Scholar 

  14. Hansch, C. and Fujita, T., J. Am. Chem. Soc.,86 (1964)1616.

    Article  Google Scholar 

  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. Kissmeyer, A.-M. and Mortensen, J.T., Xenobiotica,30 (2000)815.

    Article  PubMed  Google Scholar 

  17. Kissmeyer, A.-M., Mathiasen, I.S., Latini, S. and Binderup, L., Endocrine, 3 (1995)263.

    Google Scholar 

  18. Kissmeyer, A.-M., Preclinical pharmacokinetics and metabolism of EB1089 and other vitamin D analogs, Leo Pharmaceutical Products Ltd, Denmark,2000.

    Google Scholar 

  19. Burden, F.R., J. Chem. Inf. Comput. Sci.,29 (1989)225.

    Article  Google Scholar 

  20. Pearlman, R.S. and Smith, K.M., Perspect. Drug Discov. Des., 9/10/11 (1998)339.

  21. Ponder, J.W. and Richards, F.M., J. Comput. Chem., 8 (1987) 1016.

    Article  Google Scholar 

  22. Halgren, T.A., J. Comput. Chem.,20 (1999)720.

    Article  Google Scholar 

  23. Halgren, T.A., J. Comput. Chem.,20 (1999)730.

    Article  Google Scholar 

  24. Qiu, D., Shenkin, P.S., Hollinger, F.P., Still W.C., J. Phys. Chem. A,101 (1997)3005.

    Article  Google Scholar 

  25. Stewart, J.J.P., J. Comput. Chem.,10 (1989)209.

    Article  Google Scholar 

  26. Sutter, J.M. and Kalivas, J.H., Microchem. J.,47 (1993)60.

    Article  Google Scholar 

  27. Nørgaard, L., Saudland, A., Wagner, J., Nielsen, J.P., Munck, L. and Engelsen, S.B., Appl. Spectrosc.,54 (2000)413.

    Article  Google Scholar 

  28. Höskuldsson, A., Chemometr. Intell. Lab.,23 (1994) 1.

    Article  Google Scholar 

  29. Baroni, M., Clementi, S., Cruciani, G., Costantino, G. and Riganelli, D., J. Chemometr., 6 (1992)347.

    Article  Google Scholar 

  30. Baroni, M., Costantino, G., Cruciani, G., Riganelli, D., Valigi, R. and Clementi, S., Quant. Struct.-Act. Rel.,12 (1993) 9.

    Google Scholar 

  31. Holland J.H. (Ed.) Adaption in Natural and Artificial Systems. University of Michigan Press, Am Arbor, Michigan,1975.

    Google Scholar 

  32. Martens, H. and Martens, M., Food Qual. Prefer.,11 (2000) 5.

    Article  Google Scholar 

  33. Wold, S., Technometrics,20 (1978)397.

    Google Scholar 

  34. Haaland, D.M. and Thomas, E.V., Anal. Chem.,60 (1988) 1193.

    Article  Google Scholar 

  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. Dilworth, F.J., Calverley, M.J., Kakin, H.L.J. and Jones, G., Biochem. Pharmacol.,47 (1994)987.

    Article  PubMed  Google Scholar 

  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. Wessel, M.D., Jurs, P.C., Tolan, J.W. and Muskal, S.M., J. Chem. Inf. Comput. Sci.,38 (1998)726.

    Article  PubMed  Google Scholar 

  39. Yoshida, F. and Topliss, J.G., J. Med. Chem., 43 (2000) 2575.

    Article  PubMed  Google Scholar 

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Jensen, B.F., Sørensen, M.D., Kissmeyer, AM. et al. Prediction of in vitro metabolic stability of calcitriol analogs by QSAR. J Comput Aided Mol Des 17, 849–859 (2003). https://doi.org/10.1023/B:JCAM.0000021861.31978.da

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