title: De novo design of VEGFR-2 tyrosine kinase inhibitors based on a linked-fragment approach.
abstract: Vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors have been demonstrated to possess substantial antitumor activity. VEGFR-2 tyrosine kinase inhibitors are crucial for development of antitumor drugs. Based on the crystal structure of VEGFR-2 tyrosine kinase, a linked-fragment strategy was employed to design novel VEGFR-2 tyrosine kinase inhibitors, and 1000 compounds were generated in this process. Absorption, distribution, metabolism, excretion and toxicity (ADMET) were used to screen the 1000 compounds, and 59 compounds were acceptable. Scaffold hopping was then used for further screening, and only four compounds were obtained in this way. Then, the binding energy of the four molecules to VEGFR-2 tyrosine kinase was calculated using molecular docking, and their values were found to be lower than that of Sorafenib. Finally, molecular dynamics simulations were performed on the complex of the compound with the lowest binding energy with VEGFR-2 tyrosine kinase, and the binding model was analyzed. At the end, four chemical entities with novel structures were obtained, and were suggested for experimental testing in future studies.
authors: College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, People's Republic of China.
authors: Yi-Zhou
authors: YZ
authors: Liu
authors: College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, People's Republic of China.
authors: Xiao-Li
authors: XL
authors: Wang
authors: College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, People's Republic of China.
authors: Xin-Ying
authors: XY
authors: Wang
authors: Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China.
authors: Ri-Lei
authors: RL
authors: Yu
authors: College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, People's Republic of China.
authors: Dong-Qing
authors: DQ
authors: Liu
authors: College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, People's Republic of China. cmkang@qust.edu.cn.
authors: Cong-Min
authors: CM
authors: Kang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D015195:Drug Design; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: ADMET; Linked-fragment approach; Molecular dynamics simulations; Scaffold hopping; VEGFR-2 tyrosine kinase inhibitors