Pushing the boundaries of 3D-QSAR

Based primarily on further studies of a collection of eleven publications reporting fifteen successful 3D-QSAR relations, several phenomena are preliminarily described. The RMS error of 133 ligand binding energy predictions based on these successful 3D-QSARs is 0.75 kcal/mole, which compares favorably to the prediction accuracies of approaches that include the receptor. A similar result is obtained when topomer alignments are substituted for those published, with seemingly profound implications for the future of 3D-QSAR. The "alignment-averaged" molecular properties, log P and molar refractivity, have very little correlative power for these data sets, either alone or in combination with the 3D-QSAR field descriptors. The q(2) stopmetric for the number of PLS components necessarily tends to discard any unique or unconfirmed SAR information. Large drops in q(2) are thus to be expected whenever such unique information is first encountered. Predictive r(2) values from an exploratory new "series trajectory" analysis of these 3D-QSAR though highly variable do not differ much from their q(2) values, a phenomenon that seems to encourage prediction even when there are so few structures underlying a 3D-QSAR so that almost all information is unique.