Novel receptor surface approach for 3D-QSAR: the weighted probe interaction energy method.

A 3D-QSAR technique, called the WeP (weighted probe interaction energy) method, has been developed based on the notion that certain regions of the receptor surface contribute, to varying extents, to the differences in the activities of the ligands, while other regions do not. The probes, placed around the surface of a superimposed set of ligands, were associated with fractional weights, and then an optimal distribution of probe weights that accounts for the activity profile of the training ligands was determined using a genetic algorithm. It has been shown for the three test samples that the pseudoreceptors, which consist of the surviving probes with nonzero weight values, have good predictabilities. Especially, in the case of dihydrofolate reductase inhibitors, the pseudoreceptor resembles the real protein in that there is no surviving probe in the solvent-exposed region.