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

Abstract

A quantitative structure-activity relationship (QSAR) investigation of a set of 35 substituent-diverse quinazolines spanning an activity range of 4.16 log (1/I50 [median inhibitory concentration]) U was carried out using molecular shape analysis (MSA). I50 is the molar concentration necessary for 50% inhibition of rat liver dihydrofolate reductase (DHFR). A correlation equation, analogous in descriptor form to those developed for 2 sets of 2,4-diaminotriazines which are DHFR inhibitors, was constructed. The correlation coefficient, r, is 0.965, and the SD is 0.360. A 2nd 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 SD = 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.