Comparison of 2D similarity and 3D superposition. Application to searching a conformational drug database

In a database of about 2000 approved drugs, represented by 10(5) structural conformers, we have performed 2D comparisons (Tanimoto coefficients) and 3D superpositions. For one class of drugs the correlation between structural resemblance and similar action was analyzed in detail. In general Tanimoto coefficients and 3D scores give similar results, but we find that 2D similarity measures neglect important structural/funtional features. Examples for both over- and underestimation of similarity by 2D metrics are discussed. The required additional effort for 3D superpositions is assessed by implementation of a fast algorithm with a processing time below 0.01 s and a more sophisticated approach (0.5 s per superposition). According to the improvement of similarity detection compared to 2D screening and the pleasant rapidity on a desktop PC, full-atom 3D superposition will be an upcoming method of choice for library prioritization or similarity screening approaches.