title: 2D and 3D similarity landscape analysis identifies PARP as a novel off-target for the drug Vatalanib.
abstract: BACKGROUND
  Searching for two-dimensional (2D) structural similarities is a useful tool to identify new active compounds in drug-discovery programs. However, as 2D similarity measures neglect important structural and functional features, similarity by 2D might be underestimated. In the present study, we used combined 2D and three-dimensional (3D) similarity comparisons to reveal possible new functions and/or side-effects of known bioactive compounds.
  
  
  RESULTS
  We utilised more than 10,000 compounds from the SuperTarget database with known inhibition values for twelve different anti-cancer targets. We performed all-against-all comparisons resulting in 2D similarity landscapes. Among the regions with low 2D similarity scores are inhibitors of vascular endothelial growth factor receptor (VEGFR) and inhibitors of poly ADP-ribose polymerase (PARP). To demonstrate that 3D landscape comparison can identify similarities, which are untraceable in 2D similarity comparisons, we analysed this region in more detail. This 3D analysis showed the unexpected structural similarity between inhibitors of VEGFR and inhibitors of PARP. Among the VEGFR inhibitors that show similarities to PARP inhibitors was Vatalanib, an oral "multi-targeted" small molecule protein kinase inhibitor being studied in phase-III clinical trials in cancer therapy. An in silico docking simulation and an in vitro HT universal colorimetric PARP assay confirmed that the VEGFR inhibitor Vatalanib exhibits off-target activity as a PARP inhibitor, broadening its mode of action.
  
  
  CONCLUSIONS
  In contrast to the 2D-similarity search, the 3D-similarity landscape comparison identifies new functions and side effects of the known VEGFR inhibitor Vatalanib.
authors.affiliation: Structural Bioinformatics Group, Charite - University Medicine Berlin & ECRC, Lindenberger Weg 80, 13125, Berlin, Germany. bjoern-oliver.gohlke@charite.de.
authors.forename: Bjoern-Oliver
authors.initials: BO
authors.lastname: Gohlke
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University Berlin, Berlin, Germany. tim@overkamp.de.
authors.forename: Tim
authors.initials: T
authors.lastname: Overkamp
authors.affiliation: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. anja.richter@charite.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Richter
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University Berlin, Berlin, Germany. antje.richter@charite.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Richter
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University Berlin, Berlin, Germany. peter.daniel@charite.de.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. peter.daniel@charite.de.|Clinical and Molecular Oncology, Max Delbrück Center for Molecular Medicine, 13125 Berlin-Buch, Berlin, Germany. peter.daniel@charite.de.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Daniel
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University Berlin, Berlin, Germany. bernhard.gillissen@charite.de.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. bernhard.gillissen@charite.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Gillissen
authors.affiliation: Structural Bioinformatics Group, Charite - University Medicine Berlin & ECRC, Lindenberger Weg 80, 13125, Berlin, Germany. robert.preissner@charite.de.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. robert.preissner@charite.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Preissner
mesh_terms: D001665:Binding Sites; D003124:Colorimetry; D019295:Computational Biology; D055808:Drug Discovery; D006801:Humans; D061986:MCF-7 Cells; D008856:Microscopy, Fluorescence; D062105:Molecular Docking Simulation; D010793:Phthalazines / Q000737:chemistry* / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C404768:vatalanib; D011065:Poly(ADP-ribose) Polymerases