Advertisement

Journal of Structural Chemistry

, Volume 50, Issue 5, pp 982–988 | Cite as

Theoretical studies of the electronic and structural features of the fragments of dihydropholate reductase inhibitors

  • E. S. Afonkina
  • E. S. Pereyaslavskaya
  • V. A. Potemkin
  • M. A. Grishina
  • G. L. Rusinov
  • O. V. Fedorova
Proceedings of the XIV Seminar On Intermolecular Interactions and Molecule Conformations

Abstract

The effects of the structural characteristics of dihydrofolate reductase (DHFR) inhibitors on their tuberculostatic activity have been analyzed. It was shown that an increase in the electron density on bonds and atoms in the ring led to an increase in the biological activity of the compounds. A correlation was found between the biological activity and the characteristics of the critical points of electron density of bonds. The 3D- and 4D-QSAR studies with the CiS algorithm revealed the pharmacophore and antipharmacophore fragments of DHFR inhibitors, and regions of the receptor that are responsible for the biological action of dihydropyrimidines were found. Receptor ligand complexes were modeled. For a series of drugs containing a podand chain, it was found that the chain performed only the transport membranotropic function because the increase in the size of molecules due to the podand chain gives rise to steric hindrances when the chain is built in the receptor cavity.

Keywords

3D- and 4D-QSAR biological activity dihydrofolate reductase inhibitor pharmacophore multiconformation analysis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    C. Hansch and T. Fujita, J. Am. Chem. Soc., 86, 616 (1964).CrossRefGoogle Scholar
  2. 2.
    A. M. Doweyko, J. Med. Chem., 31, No. 4, 1396 (1988).CrossRefGoogle Scholar
  3. 3.
    G. Schneider, K.-H. Baringhaus, and H. Kubinyi, Molecular Design: Concepts and Applications, Wiley, New York (2008).Google Scholar
  4. 4.
    G. Cruciani, R. Mannhold, H. Kubinyi, and G. Folkers, Molecular Interaction Fields: Applications in Drug Discovery and ADME Prediction, Wiley, New York (2005).Google Scholar
  5. 5.
    H. Kubinyi, Drug Discov. Today, 2, No. 5, 538 (1997).CrossRefGoogle Scholar
  6. 6.
    F. Ooms, Curr. Med. Chem., 7, No. 1, 141 (2000).Google Scholar
  7. 7.
    M. Karelson, Thesis doc. Molecular Descriptors in QSAR/QSPR, 5, 430, New York (2000).Google Scholar
  8. 8.
    V. A. Potemkin, M. A. Grishina, A. V. Belik, and O. N. Chupakhin, Khim. Farm. Zh., 36, No.o. 1, 22 (2002).Google Scholar
  9. 9.
    V. A. Potemkin, M. A. Grishina, and E. V. Bartashevich, J. Struct. Chem., 48, No. 1, 155–160 (2007).CrossRefGoogle Scholar
  10. 10.
    J. S. Blanchard, Ann. Rev. Biochem., 65, No. 6, 215 (1996).CrossRefGoogle Scholar
  11. 11.
    C. O. Kappe, Eur. J. Med. Chem., 35, 1043–1052 (2000).CrossRefGoogle Scholar
  12. 12.
    R. Li, R. Sirawaraporn, P. Chitnumsub, et al., J. Mol. Biol., 295, No. 7, 307 (2000).CrossRefGoogle Scholar
  13. 13.
    V. Potemkin and M. Grishina, Drug Discovery Today, 13, 952 (2008).CrossRefGoogle Scholar
  14. 14.
    V. A. Potemkin, E. V. Bartashevich, E. S. Pereyaslavskaya, and M. A. Grishina, Abstracts of Papers from the 13th Symp. on Intermolecular Interactions of Molecular Conformations [in Russian], St. Petersburg (2006), p. 179.Google Scholar
  15. 15.
    N. L. Allinger, Y. H. Yuh, and J. H. Lii, J. Am. Chem. Soc., 111, No. 23, 8551 (1989).CrossRefGoogle Scholar
  16. 16.
    J. H. Lii and N. L. Allinger, ibid., 8566.Google Scholar
  17. 17.
    J. H. Lii and N. L. Allinger, ibid., 8576.Google Scholar
  18. 18.
    V. A. Potemkin, M. A. Grishina, O. V. Fedorova, et al., Khim. Farm. Zh., 9, No. 3, 17 (2003).Google Scholar
  19. 19.
    E. V. Bartashevich, M. A. Grishina, V. A. Potemkin, and A. V. Belik, J. Struct. Chem., 43, 1033 (2002).CrossRefGoogle Scholar
  20. 20.
    M. W. Schmidt, K. K. Baldridge, J. A. Boatz, et al., J. Comput. Chem., 112, No. 14, 1347 (1993).CrossRefGoogle Scholar
  21. 21.
    R. F. W. Bader, Atoms in Molecules — Quantum Theory, Oxford University Press, Oxford (1990).Google Scholar
  22. 22.
    I. G. Ovchinnikova, O. V. Fedorova, G. L. Rusinov, et al., Khim. Farm. Zh., 37, No. 11, 17 (2003).Google Scholar
  23. 23.
    R. Li, R. Sirawaraporn, P. Chitnumsub, et al., J. Mol. Biol., 295, 307 (2000).CrossRefGoogle Scholar
  24. 24.
    M. A. Grishina, V. A. Potemkin, K. M. Mikushina, et al., Biomed. Khim., 50, No. 1, 68 (2004).Google Scholar
  25. 25.
    M. A. Grishina, V. A. Potemkin, G. L. Rusinov, et al., Book of Abstr. 3rd Crystallographic course at the E. Majorana Centre “From genes to drugs via crystallography,” Erice (2002), p. 48.Google Scholar
  26. 26.
    K. Mikushina, V. Potemkin, M. Grishina, and S. Laufer, Arch. Pharm. Pharm. Med. Chem., 335, 74 (2002).Google Scholar

Copyright information

© Pleiades Publishing, Ltd. 2009

Authors and Affiliations

  • E. S. Afonkina
    • 1
  • E. S. Pereyaslavskaya
    • 1
  • V. A. Potemkin
    • 1
  • M. A. Grishina
    • 1
  • G. L. Rusinov
    • 2
  • O. V. Fedorova
    • 2
  1. 1.Chelyabinsk State UniversityChelyabinskRussia
  2. 2.I. Ya. Postovskii Institute of Organic Synthesis, Ural DivisionRussian Academy of SciencesYekaterinburgRussia

Personalised recommendations