Lactobacillus DHFR inhibition

In addition to nonlinear lipophilicity relationships for the transport and distribution of drugs, nonlinear relationships on molar refractivity are frequently observed in QSAR studies of enzyme inhibition data (provided that MR values are scaled by a factor of 0.1, as usual) [60,63,64,66-68]. Two such examples are given in Eq. (63) (Escherichia coli DHFR) and Eq. (64) (Lactobacillus casei DHFR) [101]. The differences between both models could be explained after the 3D structure of the enzyme became known. Whereas all substituents of a benzyl ring contribute to biological activities in E. coli DHFR, only the 3- and 4-substituents show up in the QSAR model for L. casei DHFR but not the 5-substituents. This results from a narrower binding pocket in L. casei DHFR a (3-branched leucine hinders the accommodation of 5-substituents, whereas a more flexible methionine in the same position of E. coli DHFR opens a wider binding pocket [101] ... 

The polypeptide portion of the Lactobacillus easel DHFR, a sequence segment from Ile-38 to Val-75 which shows a local similarity to the sequence segment from Arg-55 to Ile-96 of GSH, folds to construct a part of the NADP-blndlng site In the crystal structure (27-29). Inhibition of GSH by methotrexate can be rationalized If the ATP-blndlng site of GSH Is similar In sequence and function to the NADP-blndlng site of DHFR. 

Inhibition of MTX-sensitive Lactobacillus casei DHFR by 3 -X-l-phenyl-s-triazines (37) [677]. 

C. Hansch, B. A. Hathaway, Z. R. Guo, C. D. Selassie, S. W. Dietrich, J. M. Blaney, R. Langridge, K. W. Volz, and B. T. Kaufman,/. Med. Chem., 27,129 (1984). Crystallography, QSAR and Molecular Graphics in a Comparative Analysis of the Inhibition of DHFR from Chicken Liver and Lactobacillus casei by 4,6-Diamino-l,2-dihydro-2,2-di-methyl-1 -(substituted-phenyl)-s-triazines. 

Because of the central role of dihydrofolate reductase (DHFR) in purine biosynthesis, DHFR inhibitors are important as antibacterial (trimethoprim), antimalarial, and antitumor agents (methotrexate). For a series of 5-(X-benzyl)-2,4-diaminopyrimidines 9 with several different groups X, QSAR equations were derived for the inhibition of Escherichia coli (equation 14 Xi app == experimental Inhibition constants) and of Lactobacillus casei (equation 15) in both equations the numbers 3, 4, and 5 refer to the X substituent positions at the benzyl group. " ... 

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