Identification of orthologous target pairs with shared active compounds and comparison of organism-specific activity patterns.
A systematic search for active small molecules shared by orthologous targets was carried out, leading to the identification of 803 compound-based orthologous target pairs covering a total of 938 orthologues, 358 unique targets and 98 organisms. Many orthologous target pairs were found to have substantial compound coverage, enabling the introduction of an orthologous target pairs classification including 'organism cliffs' and 'potency-retaining' pairs. A total of 158 orthologous target pairs involving human orthologues were identified, which were typically associated with drug discovery-relevant targets, organism combinations and compound data. Orthologous target pairs with human orthologues included 83 potency-retaining orthologous target pairs covering a variety of targets and organisms. On the basis of these orthologous target pairs, the compound search was further extended and 1149 potent compounds were identified that only had reported activities for non-human orthologues of 48 therapeutic targets, but not their human counterparts, hence providing a large pool of candidate compounds for further evaluation. The complete set of orthologous target pairs identified in our analysis, the orthologous target pairs classification including associated data and all candidate compounds are made freely available.
Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, Bonn, D-53113, Germany.
Dilyana
D
Dimova
Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, Bonn, D-53113, Germany.
Dagmar
D
Stumpfe
Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, Bonn, D-53113, Germany.
Jürgen
J
Bajorath
D000818:Animals; D057225:Data Mining / Q000379:methods*; D062313:Databases, Pharmaceutical; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D058990:Molecular Targeted Therapy; D064798:Polypharmacology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013045:Species Specificity
D008024:Ligands; D054852:Small Molecule Libraries
active compounds; compound design; compound-based target relationships; organism cliffs; organisms; orthologous target pairs; orthologues; potency variation; targets