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. 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
