De novo design of VEGFR-2 tyrosine kinase inhibitors based on a linked-fragment approach |
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Authors: | Yi-zhou Liu Xiao-li Wang Xin-ying Wang Ri-lei Yu Dong-qing Liu Cong-min Kang |
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Affiliation: | 1.College of Chemical Engineering,Qingdao University of Science and Technology,Qingdao,People’s Republic of China;2.Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy,Ocean University of China,Qingdao,People’s Republic of China |
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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. |
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