Multivariate analysis and quantitative structure-activity relationships. Inhibition of dihydrofolate reductase and thymidylate synthetase by quinazolines

Abstract

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