Fuzzy tricentric pharmacophore fingerprints. 1. Topological fuzzy pharmacophore triplets and adapted molecular similarity scoring schemes.

This paper introduces a novel molecular description--topological (2D) fuzzy pharmacophore triplets, 2D-FPT--using the number of interposed bonds as the measure of separation between the atoms representing pharmacophore types (hydrophobic, aromatic, hydrogen-bond donor and acceptor, cation, and anion). 2D-FPT features three key improvements with respect to the state-of-the-art pharmacophore fingerprints: (1) The first key novelty is fuzzy mapping of molecular triplets onto the basis set of pharmacophore triplets: unlike in the binary scheme where an atom triplet is set to highlight the bit of a single, best-matching basis triplet, the herein-defined fuzzy approach allows for gradual mapping of each atom triplet onto several related basis triplets, thus minimizing binary classification artifacts. (2) The second innovation is proteolytic equilibrium dependence, by explicitly considering all of the conjugated acids and bases (microspecies). 2D-FPTs are concentration-weighted (as predicted at pH=7.4) averages of microspecies fingerprints. Therefore, small structural modifications, not affecting the overall pharmacophore pattern (in the sense of classical rule-based assignment), but nevertheless triggering a pKa shift, will have a major impact on 2D-FPT. Pairs of almost identical compounds with significantly differing activities ("activity cliffs" in classical descriptor spaces) were in many cases predictable by 2D-FPT. (3) The third innovation is a new similarity scoring formula, acknowledging that the simultaneous absence of a triplet in two molecules is a less-constraining indicator of similarity than its simultaneous presence. It displays excellent neighborhood behavior, outperforming 2D or 3D two-point pharmacophore descriptors or chemical fingerprints. The 2D-FPT calculator was developed using the chemoinformatics toolkit of ChemAxon (www.chemaxon.com).