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.
Structural Bioinformatics Group, Institute for Molecular Biology and Bioinformatics, Charite (CBF), Arnimallee 22, 14195 Berlin, Germany. ulrike.schmidt@charite.de
Ulrike
U
Schmidt
Jessica
J
Ahmed
Elke
E
Michalsky
Michael
M
Hoepfner
Robert
R
Preissner
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