Inhibition of dihydrofolate reductase: structure-activity correlations of quinazolines based upon molecular shape analysis.

A quantitative structure-activity relationship (QSAR) investigations of a set of 35 substituent-diverse quinazolines spanning an activity range of 4.16 log (1/I50) units was carried out using molecular shape analysis (MSA). I50 is the molar concentration necessary for 50% inhibiton of rat liver dihydrofolate reductase (DHFR). A correlation equation, analogous in descriptor form to those developed for two sets of 2,4-diaminotriazines which are also DHFR inhibitors, was constructed. The correlation coefficient, r, is 0.965, and the standard deviation, s, is 0.360. A second correlation equation was developed to explain the activities of the quinazolines on the basis of their shape similarity to a 2,4-diaminotriazine in its postulated active conformation as determined in a previous study. This correlation equation is again identical in descriptor form with those previously constructed for the triazines and quinazolines; r = 0.945 and s = 0.451 for this correlation equation. The ability to quantitatively explain activity in a congeneric set of compounds using a structurally diverse reference compound indicates the potential to design new lead compounds using MSA.