Effect of the structural characteristics of dihydrofolate reductase inhibitors on their metabolic properties

Autor:	N. A. Toreeva, E. S. Afonkina, Vladimir Potemkin, G. A. Matveev, Maria Grishina, N. N. Pal’ko
Rok vydání:	2012
Předmět:	Gene isoform biology Chemistry Stereochemistry Cytochrome P450 Metabolism Prodrug Inorganic Chemistry Dihydrofolate reductase Materials Chemistry biology.protein Molecule Physical and Theoretical Chemistry Pharmacophore Binding site
Zdroj:	Journal of Structural Chemistry. 53:365-372
ISSN:	1573-8779 0022-4766
DOI:	10.1134/s0022476612020230
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::c7d7ca70fc53447a4f9eafd55d1f68e9 https://doi.org/10.1134/s0022476612020230 Zobrazit plný text záznamu Plný text ve formátu PDF