Design And Synthesis Of VEGFR-2 Daul Inhibitors

VEGFR-2 as a major receptor of VEGF that promotes angiogenesis, is closely related to a variety of diseases such as diabetic retinopathy, rheumatoid arthritis, cancer and so on, especially the growth and metastasis of tumor depend a lot on the angiogenesis and tumor multi-drug resistance is also associated with angiogenesis. Therefore, VEGFR-2 has become the ideal target for the therapy of these diseases, especially tumor.In this manuscript, based on the structure of VEGFR-2 and the structure of those inhibitors respectively, de novo design of drugs with the method of computer aided drug design was conducted. Firstly, based on the three-dimensional structure of VEGFR-2 receptor,1001 compounds were designed with the fragment build method, and then molecular docking, ADME/Tox evaluation and molecular dynamics balance analysis were tun, after that binding mode research with those high score compounds were accomplished. Secondly, based on the structure of VEGFR-2, two pharmacophores of two kinds of inhibitors were built respectively, and then the virtual screening of ZINC database were conducted. After the second time of screening, there were 50 new compounds left, and finally 47 compounds of high grade were gained after molecular docking and ADME/Tox evaluation.In order to explore the binding/unbinding mode of VEGFR-2 with it’s inhibitors, the method of steered molecular dynamics to simulate the designed compound 01-435 were used. There were two tensile directions in the SMD simulation, traditional ATP dissociation channel and allosteric pockets channel. And it was proved that the binding/dissociation process of ligand molecules tend to through the traditional ATP dissociation channels by comparing the tension size, number of hydrogen bonds, van der Waals and electrostatic interaction of this two directions.In this manuscript, a preliminary exploration on the synthesis of compound 01-435 were conducted, the inverse synthetic routes were analysised according to the structure of this compound and the synthetic route was also designed.In summary, this paper used two methods to design the dual inhibitor of VEGFR-2, and laid a good foundation for the research and development of the inhibitors.