Comparison of the Inhibition of Methotrexate-Sensitive and -Resistant Lactobacillus casei Cell Cultures With Purified Lactobacillus casei Dihydrofolate Reductase by 4,6-Diamino-1,2-Dihydro-2,2-Dimethyl-1-(3-Substituted-Phenyl)-s-Tr iazines. Use of Quantitative Structure-Activity Relationships in Making Inferences About the Mechanism of Resistance and the Structure of the Enzyme in Situ Compared With the Enzyme in Vitro

• Published in: Journal of medicinal chemistry Vol. 24; no. 12; pp. 1422 - 1429
• Main Authors: Coast, E A, Genther, C S, Dietrich, S W, Guo, Z, Hansch, C
• Format: Journal Article
• Language: English
• Published: 01-01-1981
• Subjects: Lactobacillus casei
• ISSN: 0022-2623

The inhibitory action of a set of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-substituted-phenyl)-s-tr iazines on Lactobacillus casei dihydrofolate reductase is compared with their action on methotrexate-resistant and methotrexate-sensitive cell cultures by means of quantitative structure-selectivity analysis. The analysis uncovers major differences in the steric and hydrophobic interactions of the substituents X with the three different systems. Correlation analysis is used to define the hydrophobic binding site for 3-X in the isolated enzyme. This is shown to be similar to that of the sensitive cells but different from that in the resistant cells, which have a larger hydrophobic binding site. When X has the general structure 3-CH sub(2)ZC sub(6)H sub(4)-Y (Z = O or NH), it is shown that Y does not interact with the isolated enzyme, but in the living cells, Y interacts with a molecular barrier in a way that can be quantitatively related to the molar refractivity of X. The methotrexate-resistant cells are resistant to highly hydrophilic inhibitors such as methotrexate but are not able to resist hydrophobic inhibitors. The results with the inhibition of L. casei) dihydrofolate reductase are compared with the inhibition of enzyme from bovine liver.