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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
C. Hansch and T. Fujita, J. Am. Chem. Soc., 86, 616 (1964).
A. M. Doweyko, J. Med. Chem., 31, No. 4, 1396 (1988).
G. Schneider, K.-H. Baringhaus, and H. Kubinyi, Molecular Design: Concepts and Applications, Wiley, New York (2008).
G. Cruciani, R. Mannhold, H. Kubinyi, and G. Folkers, Molecular Interaction Fields: Applications in Drug Discovery and ADME Prediction, Wiley, New York (2005).
H. Kubinyi, Drug Discov. Today, 2, No. 5, 538 (1997).
F. Ooms, Curr. Med. Chem., 7, No. 1, 141 (2000).
M. Karelson, Thesis doc. Molecular Descriptors in QSAR/QSPR, 5, 430, New York (2000).
V. A. Potemkin, M. A. Grishina, A. V. Belik, and O. N. Chupakhin, Khim. Farm. Zh., 36, No.o. 1, 22 (2002).
V. A. Potemkin, M. A. Grishina, and E. V. Bartashevich, J. Struct. Chem., 48, No. 1, 155–160 (2007).
J. S. Blanchard, Ann. Rev. Biochem., 65, No. 6, 215 (1996).
C. O. Kappe, Eur. J. Med. Chem., 35, 1043–1052 (2000).
R. Li, R. Sirawaraporn, P. Chitnumsub, et al., J. Mol. Biol., 295, No. 7, 307 (2000).
V. Potemkin and M. Grishina, Drug Discovery Today, 13, 952 (2008).
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.
N. L. Allinger, Y. H. Yuh, and J. H. Lii, J. Am. Chem. Soc., 111, No. 23, 8551 (1989).
J. H. Lii and N. L. Allinger, ibid., 8566.
J. H. Lii and N. L. Allinger, ibid., 8576.
V. A. Potemkin, M. A. Grishina, O. V. Fedorova, et al., Khim. Farm. Zh., 9, No. 3, 17 (2003).
E. V. Bartashevich, M. A. Grishina, V. A. Potemkin, and A. V. Belik, J. Struct. Chem., 43, 1033 (2002).
M. W. Schmidt, K. K. Baldridge, J. A. Boatz, et al., J. Comput. Chem., 112, No. 14, 1347 (1993).
R. F. W. Bader, Atoms in Molecules — Quantum Theory, Oxford University Press, Oxford (1990).
I. G. Ovchinnikova, O. V. Fedorova, G. L. Rusinov, et al., Khim. Farm. Zh., 37, No. 11, 17 (2003).
R. Li, R. Sirawaraporn, P. Chitnumsub, et al., J. Mol. Biol., 295, 307 (2000).
M. A. Grishina, V. A. Potemkin, K. M. Mikushina, et al., Biomed. Khim., 50, No. 1, 68 (2004).
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.
K. Mikushina, V. Potemkin, M. Grishina, and S. Laufer, Arch. Pharm. Pharm. Med. Chem., 335, 74 (2002).
Author information
Authors and Affiliations
Corresponding author
Additional information
Original Russian Text Copyright © 2009 by E. S. Afonkina, E. S. Pereyaslavskaya, V. A. Potemkin, M. A. Grishina, G. L. Rusinov, and O. V. Fedorova
__________
Translated from Zhurnal Strukturnoi Khimii, Vol. 50, No. 5, pp. 1021–1026, September–October, 2009.
Rights and permissions
About this article
Cite this article
Afonkina, E.S., Pereyaslavskaya, E.S., Potemkin, V.A. et al. Theoretical studies of the electronic and structural features of the fragments of dihydropholate reductase inhibitors. J Struct Chem 50, 982–988 (2009). https://doi.org/10.1007/s10947-009-0146-4
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10947-009-0146-4