The binding mode of sorafenib with VEGFR2 was studied using molecular docking and molecular dynamics method. The docking results show that sorafenib forms hydrogen bonds with Asp1046, Cys919, and Glu885 of VEGFR2 receptor. Molecular dynamics simulation suggests that the hydrogen bond involving Asp1046 is the most stable one, and it is almost preserved during all the MD simulation time. The hydrogen bond formed with Cys919 occurs frequently after 6？ns, while the bifurcated hydrogen bonds involving Glu885 occurs occasionally. Meantime, molecular dynamics simulations of VEGFR2 with 11 other urea-substituted aryloxy compounds have also been performed, and the results indicate that a potent VEGFR2 inhibitor should have lower interaction energy with VEGFR2 and create at least 2 hydrogen bonds with VEGFR2. 1. Introduction Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both the growth of blood vessels from preexisting vasculature (angiogenesis) and the formation of the circulatory system (vasculogenesis). VEGF binding to tyrosine kinase receptors (VEGFR) can cause itself dimerization and become activated through transphosphorylation. There are three main subtypes of VEGFR: VEGFR1, VEGFR2, and VEGFR3. Among which VEGFR2 appears to mediate almost all of the known cellular responses to VEGF. Inhibiting the tyrosine kinase VEGFR2 signaling pathway may disrupt the angiogenesis process of solid tumor, thus blocking tumor growth and spread [1]. Therefore, the design of inhibitors targeting VEGFR2 is an attractive approach for the development of new therapeutic agents. Recently, lots of VEGR2 inhibitors have been reported. Among them sorafenib (codeveloped and comarketed by Bayer and Onyx pharmaceuticals as Nexavar) is one of the potent inhibitors of VEGFR in vitro and is approved by FDA for the treatment of advanced renal cell carcinoma and advanced primary liver cancer [2, 3]. Although sorafenib treatment of melanoma cell lines and tumor xenografts leads to cell death and tumor growth delay [4–6], it has little or no antitumor activity in advanced melanoma patients when used as a single agent [7]. Moreover, its water solubility is not satisfactory [8]. Thus, there are still needs to develop new VEGFR2 inhibitors. With the development of the computational software and hardware, the usage of in silico methods, such as docking [9], QSAR, pharmacophore modeling [10], and molecular dynamics method [11], has become essential to pharmaceutical research. Abreu et al. [12] have studied the VEGFR2-selective side-chain residue
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