Identification of two potential glycogen synthase kinase 3β inhibitors for the treatment of osteosarcoma  

作　　者：Kaimin Lu Xin Wang Yuyu Chen Danfeng Liang Hao Luo Li Long Zongyue Hu Jinku Bao 

机构地区：[1]Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, SichuanUniversity, Chengdu 6101)65, Sichuan, People's Republic of China

出　　处：《Acta Biochimica et Biophysica Sinica》2018年第5期456-464,共9页生物化学与生物物理学报（英文版）

基　　金：This work was supported by the grants from the National Natural Science Foundation of China （Nos. 81373311, 31300674, 81173093, 30970643, and J1103518）.

摘　　要：Osteosarcoma is the most common primary malignant bone tumor among adolescents worldwide with high mortality rate. Glycogen synthase kinase 3β （GSK3β） is a serine/threonine kinase and is con- sidered as a validated target in osteosarcoma therapy. Therefore, the study of GSK3β inhibitors is one of the most popular fields in anti-osteosarcoma drug development. Here, the tools of bioinformatics were used to screen novel effective inhibitors of GSK3β from ZINC Drug Database. The molecular docking,, molecular dynamic simulations, MM/GBSA, and energy decomposition analysis were per- formed to identify the inhibitors. Finally, ZINC08383479 and ZINC08441251 were selected as potential GSK3β inhibitors. These two inhibitors were evaluated by GSK3β kinase inhibition assay in vitro. The inhibition of cell proliferation was tested in osteosarcoma cell lines U2OS and MG63 in vitro. The result showed that ZINC08383479 and ZINC08441251 had high inhibition activity against GSK3β. We found that CHIR99021 （a known GSK3β inhibitor）, ZINC08383479, and ZINC08441251 had significant inhibition activity in U2OS cells and MG63 cells. These findings may provide new ideas for the design of more potent GSK3β inhibitors and therapeutic targets for osteosarcoma.Osteosarcoma is the most common primary malignant bone tumor among adolescents worldwide with high mortality rate. Glycogen synthase kinase 3β （GSK3β） is a serine/threonine kinase and is con- sidered as a validated target in osteosarcoma therapy. Therefore, the study of GSK3β inhibitors is one of the most popular fields in anti-osteosarcoma drug development. Here, the tools of bioinformatics were used to screen novel effective inhibitors of GSK3β from ZINC Drug Database. The molecular docking,, molecular dynamic simulations, MM/GBSA, and energy decomposition analysis were per- formed to identify the inhibitors. Finally, ZINC08383479 and ZINC08441251 were selected as potential GSK3β inhibitors. These two inhibitors were evaluated by GSK3β kinase inhibition assay in vitro. The inhibition of cell proliferation was tested in osteosarcoma cell lines U2OS and MG63 in vitro. The result showed that ZINC08383479 and ZINC08441251 had high inhibition activity against GSK3β. We found that CHIR99021 （a known GSK3β inhibitor）, ZINC08383479, and ZINC08441251 had significant inhibition activity in U2OS cells and MG63 cells. These findings may provide new ideas for the design of more potent GSK3β inhibitors and therapeutic targets for osteosarcoma.

关 键 词：GSK3Β INHIBITOR molecular docking MD simulation osteosarcorna 

分 类 号：TP391.41[自动化与计算机技术—计算机应用技术] S854.5[自动化与计算机技术—计算机科学与技术]