Multivariate analysis and quantitative structure-activity relationships. Inhibition of dihydrofolate reductase and...

Quantitative structure-activity relationships (QSAR) have been established for the inhibition of dihydrofolate reductase and thymidylate synthetase by 2,4-diaminoquinazoline-glutamic acid analogues. For dihydrofolate reductase from both human acute lymphocytic leukemia cells and murine L1210R cells, QSAR's obtained with 50 quinazolines were similar. On the other hand, for the inhibition of thymidylate synthetase from murine L1210S cells and from Lactobacillus casei, QSAR's formulated on the basis of data measured with 33 compounds were different, indicating that the two enzymes are dissimilar. The use of multivariate statistics including cluster analysis, factor analysis, and discriminant analysis is shown to facilitate the formulation of a satisfactory correlation equation. The procedure is demonstrated by the development of QSAR for the inhibition of thymidylate synthetase.