title: Target Fishing by Cross-Docking to Explain Polypharmacological Effects.
abstract: Drugs may have polypharmacological phenomena, that is, in addition to the desired target, they may also bind to many undesired or unknown physiological targets. As a result, they often exert side effects. In some cases, off-target interactions may lead to drug repositioning or to explaining a drug's mode of action. Herein we present an in silico approach for target fishing by cross-docking as a method to identify new drug-protein interactions. As an example and proof of concept, this method predicted the peroxisome proliferator-activated receptor (PPAR)-γ as a target of ethacrynic acid, which may explain the hyperglycemic effect brought on by this molecule. The antagonistic effect of ethacrynic acid on PPAR-γ was validated in a transient transactivation assay using human HEK293 cells. The cross-docking approach also predicted the potential mechanisms of many other drug side effects and discloses new drug repositioning opportunities. These putative interactions are described herein, and can be readily used to discover therapeutically relevant drug effects.
authors.affiliation: Pharmaceutical Biology and Biotechnology, Institute of Pharmaceutical Sciences, Albert-Ludwigs University, Stefan-Meier-Str. 19, 79104 Freiburg (Germany).|Current address: Chemische Biologie, Technische Universität Dortmund, Otto-Hahn-Straße 6, 44227, Dortmund (Germany).
authors.forename: Hitesh
authors.initials: H
authors.lastname: Patel
authors.affiliation: Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, Albert-Ludwigs University, Hermann-Herder-Str. 9, 79104 Freiburg (Germany).
authors.forename: Xavier
authors.initials: X
authors.lastname: Lucas
authors.affiliation: DSM Nutritional Products Ltd., Department of Human Nutrition and Health, P.O. Box 2676, 4002 Basel (Switzerland).
authors.forename: Igor
authors.initials: I
authors.lastname: Bendik
authors.affiliation: Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, Albert-Ludwigs University, Hermann-Herder-Str. 9, 79104 Freiburg (Germany). stefan.guenther@pharmazie.uni-freiburg.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Günther
authors.affiliation: Pharmaceutical Biology and Biotechnology, Institute of Pharmaceutical Sciences, Albert-Ludwigs University, Stefan-Meier-Str. 19, 79104 Freiburg (Germany). irmgard.merfort@pharmazie.uni-freiburg.de.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Merfort
mesh_terms: D004976:Ethacrynic Acid / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D047495:PPAR gamma; D004976:Ethacrynic Acid
keywords: PPAR-γ; ethacrynic acid; high-throughput virtual screening; polypharmacology; side effects