Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis of large, flexible molecules, such as the dopamine reuptake inhibitor GBR 12909 (1), is complicated by the fact that they can take on a wide range of closely-related conformations. The first step in the analysis is to classify the conformers into groups. Over 600 conformers each of a piperazine (2) and piperidine (3) analog of 1 were generated by random search conformational analysis using the Merck Molecular Force Field (MMFF94). Singular value decomposition (SVD) was used to group the conformers of 2 and 3 by the similarity of their non-ring torsional angles. SVD uncovered subtle differences in their conformer populations due to that fact that the conformers separate along different principal components, and ultimately to the fact that different torsional angles are the chief contributors to these components. The results were compared to our previous SVD analysis (Fiorentino, et al., Journal of Computational Chemistry, 2006, 27, 609-620) of conformer populations of 2 and 3 generated by the Tripos force field and Gasteiger-Hückel charges. Except for the dominant contribution of angle B3 to principal component 8 seen with both force fields, the angles which are chiefly responsible for the grouping of the conformers of 2 and 3 are different with both force fields. This illustrates that SVD is useful in identifying unique groupings of conformers in large data sets of flexible molecules—a first step in selecting representative conformers for 3D-QSAR modeling studies.
