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Pharmaceutical Chemistry Journal

, Volume 51, Issue 10, pp 884–888 | Cite as

QSAR Modelling of Thymidylate Synthase Inhibitors in a Series of Quinazoline Derivatives

  • V. R. KhairullinaEmail author
  • A. Ya. Gerchikov
  • A. A. Lagunin
  • F. S. Zarudii
Article

Thymidylate synthase (ThS) is a target for antimetabolite antitumor drugs. Such drugs have been used in the clinic although they cause several severe side effects and accumulate in tissues. Therefore, new less toxic ThS inhibitors must be sought and created. The GUSAR 2013 program was used to study the quantitative structure – activity relationship (QSAR) of a series of antifolate ThS inhibitors in the IC50 range 0.52 – 24,800.00 nM. Statistically significant QSAR models were constructed using MNA- and QNA-descriptors and self-consistent regression. They typically predicted highly accurately the structures of the training and test sets (\( {\mathrm{R}}_{\mathrm{train}}^2 \): 0.855 – 0.922; \( {\mathrm{R}}_{\mathrm{train}}^3 \): 0.810 – 0.895;\( {\mathrm{R}}_{\mathrm{test}1}^2 \): 0.734 – 0.790; \( {\mathrm{R}}_{\mathrm{test}2}^2 \): 0.800 – 0.835).

Keywords

antifolate thymidylate synthase inhibitors QSAR GUSAR 2013 QNA- and MNA-descriptors structure—activity relationship analysis 

Notes

Acknowledgments

The work was supported financially under a state task and the Basic Research Program of the State Academies of Sciences for 2013 – 2020 (A. A. Lagunin).

References

  1. 1.
    J. Liu, J. C. Schmitz, X. Lin, et al., Biochim. Biophys. Acta, 1587(2 – 3), 174 – 182 (2002).CrossRefPubMedGoogle Scholar
  2. 2.
    P. R. Subbarayan, K. Lee, B. Ardalan, Anticancer Res., 30(4), 1157 – 1162 (2010).PubMedGoogle Scholar
  3. 3.
    J. A. van der Zee, C. H. J. van Eijck, H. van Dekken, et al., Eur. J. Surg. Oncol. (EJSO), 38(11), 1058 – 1064 (2012).CrossRefGoogle Scholar
  4. 4.
    O. M. H. Salo-Ahen, A. Tochowicz, C. Pozzi, D. Cardinale, et al., J. Med. Chem., 58(8), 3572 – 3581 (2015).CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    J. Walling, Invest. New Drugs, 24, 37 – 77 (2006).CrossRefPubMedGoogle Scholar
  6. 6.
    E. Chu, J. Biol. Chem., 265(15), 8470 – 8478 (1990).PubMedGoogle Scholar
  7. 7.
    V. J. Chen, Br. J. Cancer, 78(3), 27 – 34 (1998).CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    D. A. Filimonov and V. V. Poroikov, Ross. Khim. Zh., 50(2), 66 – 75 (2006).Google Scholar
  9. 9.
    A. V. Zakharov, A. A. Lagunin, D. A. Filimonov, et al., Chem. Res. Toxicol., 25(11), 2378 – 2385 (2012).CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    I. A. Taipov, V. R. Khairullina, A. Ya. Gerchikov, et al., Vestn. Bashkir. Univ., 17(2), 886 – 891 (2012).Google Scholar
  11. 11.
    D. A. Filimonov, A. V. Zakharov, A. A. Lagunin, et al., SAR QSAR Environ. Res., 20(7 – 8), 679 – 709 (2009).CrossRefPubMedGoogle Scholar
  12. 12.
    A. V. Zakharov., E. V. Varlamova, A. A. Lagunin, et al., Mol. Pharm., 13(2), 545 – 556 (2016).Google Scholar
  13. 13.
    V. R. Khairullina, A. Ya. Gerchikov, A. A. Lagunin, et al., Biokhimiya, 80(1), 96 – 110 (2015).Google Scholar
  14. 14.
    V. R. Khairullina, A. Ya. Gerchikov, F. S. Zarudii, et al., Vestn. Bashk. Univ., 19(2), 417 – 422 (2014).Google Scholar
  15. 15.
    P. J. Marsham, A. L. Jackman, J. Oldfield, et al., J. Med. Chem., 33(11), 3072 – 3078 (1990).CrossRefPubMedGoogle Scholar
  16. 16.
    P. J. Marsham, L. R. Hughes, A. L. Jackman, et al., J. Med. Chem., 34(5), 1594 – 1605 (1991).CrossRefPubMedGoogle Scholar
  17. 17.
    P. J. Marsham, A. L. Jackman, A. J. Hayter, et al., J. Med. Chem., 34(7), 2209 – 2218 (1991).CrossRefPubMedGoogle Scholar
  18. 18.
    P. J. Marsham, A. L. Jackman, A. J. Barker, et al., J. Med. Chem., 38(6), 994 – 1004 (1995).CrossRefPubMedGoogle Scholar
  19. 19.
    P. J. Marsham, J. M. Wardleworth, F. T. Boyle, et al., J. Med. Chem., 42(19), 3809 – 3820 (1999).CrossRefPubMedGoogle Scholar
  20. 20.
    L. F. Hennequin, F. T. Boyle, J. M. Wardleworth, et al., J. Med. Chem., 39, 695 – 704 (1996).CrossRefPubMedGoogle Scholar
  21. 21.
    L. R. Hughes, A. L. Jackman, J. Oldfield, et al., J. Med. Chem., 33(11), 3060 – 3067 (1990).CrossRefPubMedGoogle Scholar
  22. 22.
    J. C. Dearden, M. T. Cronin, K. L. Kaiser, SAR QSAR Environ. Res., 20(3 – 4), 241 – 266 (2009).CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • V. R. Khairullina
    • 1
    Email author
  • A. Ya. Gerchikov
    • 1
  • A. A. Lagunin
    • 2
    • 3
  • F. S. Zarudii
    • 4
  1. 1.Department of ChemistryBashkir State UniversityUfaRussia
  2. 2.N. I. Pirogov Russian National Research Medical UniversityMoscowRussia
  3. 3.V. N. Orekhovich Institute of Biomedical ChemistryRussian Academy of Medical SciencesMoscowRussia
  4. 4.Bashkir State Medical UniversityUfaRussia

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