Comparative VEGF receptor tyrosine kinase modeling for the development of highly specific inhibitors of tumor angiogenesis.
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-/3D-searching 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.
Schmidt
Ulrike
U
Structural Bioinformatics Group, Institute for Molecular Biology and Bioinformatics, Charite (CBF), Arnimallee 22, 14195 Berlin, Germany. ulrike.schmidt@charite.de
Ahmed
Jessica
J
Michalsky
Elke
E
Hoepfner
Michael
M
Preissner
Robert
R
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D016172:DNA Fingerprinting; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D011487:Protein Conformation; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000737:chemistry* / Q000502:physiology; D017386:Sequence Homology, Amino Acid
D020533:Angiogenesis Inhibitors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor