2D and 3D similarity landscape analysis identifies PARP as a novel off-target for the drug Vatalanib

BMC Bioinformatics

Research Article

Tim Overkamp¹  Antje Richter¹  Bernd Gillissen²  Peter T. Daniel³  Anja Richter⁴  Bjoern-Oliver Gohlke⁵  Robert Preissner⁶ 

[1]Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University Berlin, Berlin, Germany

[2]Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University Berlin, Berlin, Germany

[3]German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

[4]Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Campus Berlin-Buch, Humboldt University Berlin, Berlin, Germany

[5]German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

[6]Clinical and Molecular Oncology, Max Delbrück Center for Molecular Medicine, 13125 Berlin-Buch, Berlin, Germany

[7]German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

[8]Structural Bioinformatics Group, Charite - University Medicine Berlin & ECRC, Lindenberger Weg 80, 13125, Berlin, Germany

[9]Structural Bioinformatics Group, Charite - University Medicine Berlin & ECRC, Lindenberger Weg 80, 13125, Berlin, Germany

[10]German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany

关键词: Bioinformatics;    Drug action;    Drug discovery;    Polyadenylation;    Vascular endothelial growth factor (VEGF);    3D similarity landscapes;    Drug-discovery;    Vatalanib;    PARP;   

DOI  :  10.1186/s12859-015-0730-x

 received in 2015-05-20, accepted in 2015-09-08,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundSearching 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.ResultsWe 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.ConclusionIn contrast to the 2D-similarity search, the 3D-similarity landscape comparison identifies new functions and side effects of the known VEGFR inhibitor Vatalanib.

【 授权许可】

CC BY   
© Gohlke et al. 2015