title: Growth of ligand-target interaction data in ChEMBL is associated with increasing and activity measurement-dependent compound promiscuity.
abstract: Compounds with high-confidence target annotations and activity measurements in the original and current release of the ChEMBL database have been compared to better understand how the growth of compound activity data might influence the spectrum of ligand-target interactions and the degree of target promiscuity among active compounds. Compared to the original ChEMBL release, a significant increase in the proportion of target promiscuous compounds was observed in the current version. The presence of these compounds led to large-magnitude changes in compound activity-based target and target family relationships and to a reorganization of major target communities. Surprisingly, however, this strong trend toward increasing target promiscuity was largely caused by growth of compounds with exclusive IC(50) measurements. By contrast, compounds with available equilibrium constants, which were also added in large amounts, did not substantially alter compound-based target relationships and notably contribute to increasing target promiscuity. These findings suggest that apparent compound promiscuity is much dependent on experimental conditions under which activities are determined and that care should be taken when evaluating promiscuity and polypharmacology on the basis of assay-dependent activity measurements.
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, D-53113 Bonn, Germany.
authors.forename: Ye
authors.initials: Y
authors.lastname: Hu
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D062126:Databases, Chemical; D062313:Databases, Pharmaceutical; D019277:Entropy; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D018401:Sample Size; D013329:Structure-Activity Relationship
chemical_list: D001688:Biological Products; D008024:Ligands