De novo Design of Indole Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors

Protein tyrosine kinase(PTK) is an especially important target for anticancer drug design due to 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-2 tyrosine kinase are potential chemotherapeutics to treat tumors. In this study, based on the crystal structure of VEGFR-2 tyrosine kinase, de novo drug design was employed to develop a series of indole compounds. Absorption, distribution, metabolism, excretion and toxicity(ADMET) and molecular docking were used to screen the designed compounds. Finally, ten molecules which have lower binding energy were obtained, a 10 us molecular dynamics(MD) calculation was performed to study the complex of the compound which has the lowest binding energy and VEGFR-2 tyrosine 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-2 tyrosine kinase inhibitors.