Direct prediction of dissociation constants (pKa's) of clonidine-like imidazolines, 2-substituted imidazoles and 1-methyl-2-substituted-imidazoles from 3D structures using a comparative molecular field analysis (CoMFA) approach

The applicability of a comparative molecular field analysis (CoMFA) method to reproduce and predict the pKa values of 28 clonidine-like imidazoline analogues and 16 2-substituted imidazoles has been investigated with the GRID force field. Molecular fields calculated with an H+ probe and AM1 partial atomic charges produced a correlation with a small standard deviation and a high correlation coefficient with cross validation. It was concluded that the CoMFA treatment of electrostatic effects is suitable for predicting pKa values and thus for the examination of the electronic effects in 3D quantitative structure-activity relationships.