Inhibition of dihydrofolate reductase: structure-activity correlations of 2,4-diamino-5-benzylpyrimidines based upon molecular shape analysis

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Abstract
A quantitative structure-activity relationship (QSAR) investigation of a set of 23 substituted 2,4-diamino-5-benzylpyrimidines spanning an activity range of 1.8 log (1/C) units was carried out using molecular shape analysis (MSA). C is the molar concentration necessary for 50% inhibition of bovine liver dihydrofolate reductase (DHFR). The active shape of these compounds was deduced by comparing the change in conformational state to the activity of 4 compounds outside the data base described above. A correlation equation, analogous in descriptor form to those developed earlier for DHFR inhibition by substituted 2,4-diaminotriazines and -quinazolines, was constructed. The correlation coefficient, r, was 0.931 and the SD of fit, s, was 0.137. These pyrimidines apparently bind to DHFR with shape features different from both the triazines and quinazolines. The active shape of the pyrimidines suggests that it is preferable to substitute at the meta position of the benzyl ring rather than at the para position.