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
Keywords: 3D- and 4D-QSAR, biological activity, dihydrofolate reductase, inhibitor, pharmacophore, multiconformation analysis
Pages: 1022-1026
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.
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