A general distance-geometry three-dimensional receptor model for diverse dihydrofolate reductase inhibitors

Abstract

A common 3-dimensional receptor model was formulated for 6 different classes of rat liver dihydrofolate reductase inhibitors using the distance geometry approach. Sixty-two molecules of 5 different classes were used to generate the receptor model, which has 11 attractive site points and 5 repulsive ones. It gave a fit having a correlation coefficient of 0.949 and root mean square (rms) derivation of 0.527. The attractive site points of the model closely correspond to the one reported earlier. The model successfully predicted the biological data of 33 molecules of 5 different classes, one molecule of which was a member of a new class not included in the original data set. Guidelines are put forth for the synthesis of improved inhibitors.