EFFECT OF THE STRUCTURAL CHARACTERISTICS OF DIHYDROFOLATE REDUCTASE INHIBITORS ON THEIR METABOLIC PROPERTIES
E. S. Afon'kina, N. N. Pal'ko, G. A. Matveev, N. A. Toreeva, V. A. Potemkin, M. A. Grishina
Keywords: structure-property relationship, molecular docking, dihydrofolate reductase, conformational analysis, shortened contacts, metabolites, "receptor-ligand" complex, tuberculostatic agents
Pages: 364-371
Abstract
The orientation of dihydropyrimidine derivatives containing podand chains is determined in the model receptor using the CiS algorithm. The orientation of compounds with podand chains is compared with the location of compounds without podand chains in the model receptor. The pharmacophore and antipharmacophore parts of the compounds are analyzed. Amino acid residues responsible for the effective interactions of the compounds with podand chains with the binding site of dihydrofolate reductase (DHFR) are identified using the X-ray diffraction data. The mechanism of the action of tuberculostatic compounds with podand chains in their composition is proposed, which assumes the studied molecules to undergo metabolism by cytochrome P450 isoform 3A4 forming metabolites. The most active are the metabolites without the fragments of podand chains, which interact with DHFR. Therefore, the compounds containing podand chains are prodrugs.
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