A new topomer-based method for 3D searching of conventional structural databases is described, according to which 3D molecular structures are compared as sets of fragments or topomers, in single rule-generated conformations oriented by superposition of their fragmentation bonds. A topomer is characterized by its CoMFA-like steric shape and now also by its pharmacophoric features, in some novel ways that are detailed and discussed. To illustrate the behavior of topomer similarity searching, a new dbtop program was used to generate a topomer distance matrix for a diverse set of 26 PDE4 inhibitors and 15 serotonin receptor modulators. With the best of three parameter settings tried, within the 210 shortest topomer distances (of 1460), 94.7% involved pairs of compounds having the same biological activity, and the nearest neighbor to every compound also shared its activity. The standard similarity metric, Tanimoto coefficients of "2D fingerprints", could achieve a similar selectivity performance only for the 108 shortest distances, and three Tanimoto nearest neighbors had a different biological activity. Topomer similarity also allowed "lead-hopping" among 22 of the 26 PDE4 inhibitors, notably between rolipram and cipamfylline, while 2D fingerprints" Tanimotos recognized similarity only within generally recognized structural classes. In 370 searches of authentic high-throughput screening (HTS) data sets, the typical topomer similarity search rate was about 200 structures per s.