This presentation introduces a novel tricentric pharmacophore descriptor – topological (2D) Fuzzy Pharmacophore Triplets, 2D-FPT, featuring several key improvements with respect to state-of-the-art pharmacophore fingerprints:pKa-dependent, -fuzzy pharmacophore feature detection.- fuzzy mapping of molecular triplets onto the basis set of pharmacophore triplets.-a novel similarity scoring scheme, accounting for simultaneously populated, simultaneously absent and differently populated triplets in molecule pairs.-The 2D-FPT monitor the population of topological pharmacophore triplets in molecules, with the number of interposed bonds serving as the measure of distance between the features. The original fuzzy pharmacophore feature assignment procedure reported here, relying on the predicted populations of ionized species at pH=7.4, has proven a better strategy than classical rule-based classification of functional groups into pharmacophore categories. It allows the 2D-FPT-based similarity score to correctly explain many unexpected activity differences observed between structurally almost identical compound pairs, thus assumed to be close neighbors by classical similarity scores. Moreover, this original 2D-FPT similarity scoring scheme (classical dissimilarity metrics failed to work with such high-dimension sparse fingerprints!) was shown to display excellent Neighborhood Behavior, outperforming 2D or 3D two-point pharmacophore descriptors or chemical fingerprints. The key innovation it features relies on the acknowledgment that simultaneous absence of a triplet in both molecules is a less constraining indicator of similarity than its simultaneous presence. Neighborhood Behavior benchmarking studies were conducted with respect to activity profile similarities of drug and reference molecules of the BioPrint® database. On this occasion, a novel metric of the similarity of two experimental activity profiles has been introduced. 2D-FPT were also successfully validated in active analog retrieval experiments from seeded compound collections. The 2D-FPT calculator was developed using the chemoinformatics developer's toolkit of ChemAxon (www.chemaxon.com) Download