Combined distance geometry analysis of dihydrofolate reductase inhibition by quinazolines and triazines

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Abstract
Guided by the success of distance geometry in explaining the inhibition of dihydrofolate reductase by 68 quinazolines, a combined analysis on the inhibition of rat liver dihydrofolate reductase by 33 triazines and 15 quinazolines was made. The model gave a fit having r = 0.892 and root mean square (rms) deviation 0.596 in log (1/C50) units. The model was applied to predict the biological activity of 91 compounds. The predicted values showed a rms deviation of 0.907 and a correlation coefficient of 0.790. The present study suggested the synthesis of some triazines as possible potent dihydrofolate inhibitors. The site geometry was compared with the crystal structure of a triazine bound to chicken liver dihydrofolate reductase and a good correlation was found.