Design Vascular Endothelial Growth Factor Receptor-2 Receptor Tyrosine Kinase Inhibitors

Angiogenesis is of great importance to a variety of normal physiological processes and pathological disorders. It is tightly regulated by many mechanisms, among which vascular endothelial growth factor (VEGF) is one of the most potent promoters. VEGF binds and activates its specific receptor tyrosine kinases, especially vascular endothelial growth factor receptor-2(VEGFR-2). VEGFR-2 mediates the key functional and biochemical effects of VEGF in endothelial cells including proliferation, migration, survival, and permeability. Research and development of VEGFR-2 inhibitors in order to prohibit angiogenesis has become a significant strategy for cancer therapy, as well as other diseases treatment.Computer aided drug design method was used to research the structure-activity relationship of benzimidazole derivatives, which were novel VEGFR-2 inhibitors. As a result, pharmacophore models were established, the informations concerning how to improve the inhibiting activity were also obtained. As a preparatory work for research and development of VEGFR-2 inhibitors, this research will provide a good foundation for the subsequent research. This paper includes four parts:Part one, introduction. VEGF/VEGFR-2 signaling pathway mechanisms and VEGFR-2 inhibitors research progress were introduced in brief. The theory of computer aided drug design was also summarized.Part two, benzimidazole derivatives were researched to establish pharmacophore models. A distance comparison method was used as the arithmetic. The pharmacophore model, which with the highest score, was refined and validated later.Part three, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to do three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis of benzimidazole derivatives. CoMFA and CoMSIA models were builded and validated. With good predicted ability, those models could be useful for improving this kind of inhibitors.Part four, as a assume, 1,8-naphthyridine derivatives were design as novel VEGFR-2 inhibitors.