title: Inverse in silico screening for identification of kinase inhibitor targets.
abstract: Protein kinases are clinically relevant, attractive drug targets for cancer. One major problem with kinase inhibitors is broad promiscuity, causing off-target actions and side effects. In silico prediction of targets of a compound would immensely facilitate and accelerate drug development. Using a virtual "inverse" screening approach, where single compounds are docked into protein structures from a database, we identify among known targets of indirubin derivatives phosphoinositide-dependent kinase 1 (PDK1) as a target of one derivative (6BIO) in particular. This prediction is functionally supported by an in vitro kinase assay, inhibition of intracellular phosphorylation of PDK1-substrates, and inhibition of endothelial cell migration, which highly depends on PDK1. Virtual inverse screening combined with biological tests, thus, is proposed as a valuable tool for the drug discovery process and re-examination of already established kinase inhibitors.
authors.affiliation: Pharmaceutical Biology, Department of Pharmacy, University of Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
authors.forename: Simon
authors.initials: S
authors.lastname: Tietze
authors.forename: Frank
authors.initials: F
authors.lastname: Totzke
authors.forename: Michael
authors.initials: M
authors.lastname: Kubbutat
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.forename: Joannis
authors.initials: J
authors.lastname: Apostolakis
mesh_terms: D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D007211:Indoles; D010091:Oximes; C000631429:PDK1 protein, human; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C474021:indirubin-3'-monoxime; D017346:Protein Serine-Threonine Kinases