Quantitative structure-activity relationship by distance geometry: quinazolines as dihydrofolate reductase inhibitors

This is a reinvestigation of 68 quinazoline inhibitors of dehydrofolate reductase. As in the earlier study, the binding data fitted to an 11-point model of the site, but improved computer algorithms resulted in a much better overall fit (correlation coefficient 0.95, standard deviation 0.727 kcal) and a more accurate fit for some very loosely bound 2,4-diaminoquinazolines. Removal of two of the site points (numbers 5 and 9) gave an even better fit than the original 11 site points. However, deleting a third one (number 8) worsened the calculated binding energies of the loosely bound 2,4-diaminoquinazolines. The results lead to predictions of chemical modifications of the quinazolines that should improve their biological activity.