title: Computational polypharmacology analysis of the heat shock protein 90 interactome.
abstract: The design of a single drug molecule that is able to simultaneously and specifically interact with multiple biological targets is gaining major consideration in drug discovery. However, the rational design of drugs with a desired polypharmacology profile is still a challenging task, especially when these targets are distantly related or unrelated. In this work, we present a computational approach aimed at the identification of suitable target combinations for multitarget drug design within an ensemble of biologically relevant proteins. The target selection relies on the analysis of activity annotations present in molecular databases and on ligand-based virtual screening. A few target combinations were also inspected with structure-based methods to demonstrate that the identified dual-activity compounds are able to bind target combinations characterized by remote binding site similarities. Our approach was applied to the heat shock protein 90 (Hsp90) interactome, which contains several targets of key importance in cancer. Promising target combinations were identified, providing a basis for the computational design of compounds with dual activity. The approach may be used on any ensemble of proteins of interest for which known inhibitors are available.
authors: †Life Sciences Department, University of Modena and Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
authors: Andrew
authors: A
authors: Anighoro
authors: ‡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: Dagmar
authors: D
authors: Stumpfe
authors: ‡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: Kathrin
authors: K
authors: Heikamp
authors: §Urological Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, United States.
authors: Kristin
authors: K
authors: Beebe
authors: §Urological Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, United States.
authors: Leonard M
authors: LM
authors: Neckers
authors: ‡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: Jürgen
authors: J
authors: Bajorath
authors: †Life Sciences Department, University of Modena and Reggio Emilia, Via Campi 183, 41125 Modena, Italy.
authors: Giulio
authors: G
authors: Rastelli
mesh_terms: D001665:Binding Sites; D062126:Databases, Chemical; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D064798:Polypharmacology; D060066:Protein Interaction Maps; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D047628:Estrogen Receptor alpha; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human