Design And Synthesis Of Indole Derivatives As Vegfr-2Tyrosine Kinase Inhibitors

Protein tyrosine kinase (PTK) is an especially important target for anticancer drug design because of its crucial role in the modulation of growth factor signaling. Vascular endothelial growth factor receptor-2(VEGFR-2) tyrosine kinase plays a pivotal role in modulating angiogenesis, as well as the proliferation and migration of endothelium. Compounds that inhibit the activity of VEGFR-2tyrosine kinase are potential chemotherapeutics to treat tumors.In this study, based on the crystal structure of vascular endothelial growth factor receptor-2(VEGFR-2) tyrosine kinase, de novo drug design has been employed to develop a series of indole compounds. ADMET and molecular docking were used to screen the designed compounds. Finally, ten molecules which have lower binding energy were obtained, a10ns molecular dynamics (MD) calculation was performed to study the complex of the compound which has the lowest binding energy and VEGFR-2tyrosine kinase, and then the binding models were analyzed. These new chemical entities could be lead compounds for anticancer. This result will provide theoretical basis for molecular structure improvement, molecular design, and molecular synthesis of VEGFR-2tyrosine kinase inhibitors.Then based on the structure of vascular endothelial growth factor receptor-2(VEGFR-2) tyrosine kinase active and inactive conformation, de novo drug design has been employed to develop a series of indole compounds. ADMET and molecular docking were used to screen the designed compounds. Finally, seven indole derivatives which can inhibit both VEGFR-2tyrosine kinase active and inactive conformation were obtained, and both binding models were analyzed. These new chemical entities could be lead compounds for anticancer. This result will provide theoretical basis for molecular structure improvement, molecular design, and molecular synthesis of VEGFR-2tyrosine kinase dual inhibitors.The retro synthesis routes of the compounds were analyzed, and the reasonable synthetic routes were designed. The synthesis for indole derivatives was explored, and the foundation for the synthesis of target compounds was laid.