2D and 3D similarity landscape analysis identifies PARP as a novel off-target for the drug Vatalanib was written by Gohlke, Bjoern-Oliver;Overkamp, Tim;Richter, Anja;Richter, Antje;Daniel, Peter T.;Gillissen, Bernd;Preissner, Robert. And the article was included in BMC Bioinformatics in 2015.Formula: C20H15ClN4 This article mentions the following:
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 utilized 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 analyzed this region in more detail. This 3D anal. 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 mol. protein kinase inhibitor being studied in phase-III clin. 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. Conclusion: In contrast to the 2D-similarity search, the 3D-similarity landscape comparison identifies new functions and side effects of the known VEGFR inhibitor Vatalanib. In the experiment, the researchers used many compounds, for example, N-(4-Chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine (cas: 212141-54-3Formula: C20H15ClN4).
N-(4-Chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine (cas: 212141-54-3) belongs to phthalazine derivatives. Like many other isomeric benzodiazines, phthalazine derivatives reveal numerous pharmacological and biological activities such as anticonvulsant, antitumor, antiproliferative, antiepileptic, anti-inflammatory, and vasorelaxant. Phthalazine derivatives are also considered as p38MAP kinase inhibitors, selective binders of gamma-aminobutyric acid (GABA) receptors, cyclooxygenase-2 (COX-2) inhibitors, and high-affinity ligands of voltages gated calcium channels.Formula: C20H15ClN4
Referemce:
Phthalazine – Wikipedia,
Phthalazine | C8H6N2 – PubChem