Comparison of the inhibition of Escherichia coli and Lactobacillus casei dihydrofolate reductase by 2,4-diamino-5-(substituted-benzyl)pyrimidines: quantitative structure-activity relationships, x-ray crystallography, and computer graphics in structure-activity analysis

1982 ◽  
Vol 25 (7) ◽  
pp. 777-784 ◽  
Author(s):  
Corwin Hansch ◽  
Renli Li ◽  
Jeffrey M. Blaney ◽  
Robert Langridge
Keyword(s):  
Escherichia Coli ◽  
Computer Graphics ◽  
Dihydrofolate Reductase ◽  
Lactobacillus Casei ◽  
Activity Analysis ◽  
Quantitative Structure ◽  
X Ray ◽  
X Ray Crystallography ◽  
Structure Activity ◽  
Quantitative Structure Activity Relationships

Dihydrofolate Reductase Inhibition. A Study in the Use of X-ray Crystallography, Molecular Graphics, and Quantitative Structure-Activity Relations in Drug Design

1982 ◽  
Vol 16 (5) ◽  
pp. 391-396 ◽  
Author(s):  
Corwin Hansch
Keyword(s):  
Cell Culture ◽  
Dihydrofolate Reductase ◽  
Three Dimensional ◽  
Bovine Liver ◽  
Quantitative Structure ◽  
Molecular Graphics ◽  
X Ray ◽  
X Ray Crystallography ◽  
Structure Activity ◽  
Hydrophobic Barrier

Substituent constants and regression analyses are used to formulate quantitative structure-activity relationships (QSAR) for the inhibition by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-X-phenyl)- s-triazines of purified dihydrofolate reductase (DHFR) from L. casei cells, bovine liver, and murine leukemia cells (L5178Y). The QSAR for the activity of the triazines on purified DHFR is compared with the QSAR for their action on L. casei cell culture and murine L5178Y cell culture. The QSAR for action on purified DHFR is similar to that on wild type cells; however, the QSAR for these cells differs remarkably from QSAR for both types of cells that are resistant to methotrexate (MTX). The conclusion from these analyses is that cells resistant to MTX protect themselves from this highly hydrophilic drug by developing a hydrophobic barrier. Our understanding of DHFR interaction with drugs is rapidly increasing via QSAR, and X-ray crystallography, combined with the new molecular graphics of Langridge's group, promises to expedite the process. The value of three-dimensional color graphics is discussed, with the aid of color stereo views of L. casei and E. coli DHFR.

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