Comparative VEGF Receptor Tyrosine Kinase Modeling for the Development of Highly Specific Inhibitors of Tumor Angiogenesis

Ulrike Schmidt[1] (ulrike.schmidt@charite.de)
Jessica Ahmed[1] (jessica.ahmed@charite.de)
Elke Michalsky[1] (elke.michalsky@charite.de)
Michael Hoepfner[2] (michael.hoepfner@charite.de)
Robert Preissner[1] (robert.preissner@charite.de)

[1] Structural Bioinformatics Group, Institute for Molecular Biology and Bioinformatics, Charite (CBF), Arnimallee 22, 14195 Berlin, Germany
[2] Molecular Tumor Therapy and Tumor Angiogenesis Group, Institute of Physiology, Charite (CBF), Arnimallee 22, 14195 Berlin, Germany


Abstract

The Vascular Endothelial Growth Factor receptors (VEGF-Rs) play a significant role in tumor development and tumor angiogenesis and are therefore interesting targets in cancer therapy. Targeting the VEGF-R is of special importance as the feed of the tumor has to be reduced. In general, this can be carried out by inhibiting the tyrosine kinase function of the VEGF-R. Nevertheless, there arise some problems with the specificity of known kinase inhibitors: they bind to the ATP-binding site and inhibit a number of kinases, moreover the so far most specific inhibitors act at least on these three major types of VEGF-Rs: Flt-1, Flk-1/KDR, Flt-4. The goal is a selective VEGF-R-2 (Flk-1/KDR) inhibitor, because this receptor triggers rather unspecific signals from VEGF-A, -C, -D and -E. Here, we describe a protocol starting from an established inhibitor (Vatalanib) with 2D-/3Dsearching and property filtering of the in silico screening hits and the “negative docking approach”. With this approach we were able to identify a compound, which shows a fourfold higher reduction of the proliferation rate of endothelial cells compared to the reduction effect of the lead structure.

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Japanese Society for Bioinformatics