title: Reduction and recombination of fingerprints of different design increase compound recall and the structural diversity of hits.
abstract: We report an advanced 'hybrid fingerprint' design concept specifically for the purpose of scaffold hopping. The generation of hybrid fingerprints includes two major steps. In the 'fingerprint reduction' step, bit positions of different types of fingerprints (e.g. substructural and pharmacophore fingerprints) are ranked according to their statistical significance and ability to discriminate between specifically active compounds and database decoys. On the basis of bit ranking, subsets containing the most discriminatory bit positions are determined. In the subsequent 'fingerprint recombination' step, bit subsets from different fingerprints are combined to yield a new compound class-directed fingerprint representation for similarity searching. Here, we generate hybrids from multiple fingerprints and analyze their search performance in comparison with parental fingerprints on compound activity classes that exclusively consist of molecules with unique core structures and that exhibit different levels of intra-class structural diversity. Fingerprint reduction is found to be a critical component of hybrid design. The resulting compound class-directed hybrid fingerprints further increase the similarity search performance and scaffold hopping potential of their parental fingerprints. Thus, fingerprint reduction and recombination improve compound recall and increase the structural diversity of hits.
authors.affiliation: Department of Life Science Informatics, Rheinische Friedrich-Wilhelms-Universität Bonn, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Nisius
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D000465:Algorithms; D020650:Combinatorial Chemistry Techniques; D016208:Databases, Factual; D015195:Drug Design; D008956:Models, Chemical; D013329:Structure-Activity Relationship