Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, People's Republic of China.
Acta Biochim Biophys Sin (Shanghai). 2018 May 1;50(5):456-464. doi: 10.1093/abbs/gmx142.
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 considered 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 performed 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.
骨肉瘤是全球青少年中最常见的原发性恶性骨肿瘤，死亡率很高。糖原合酶激酶 3β（GSK3β）是一种丝氨酸/苏氨酸激酶，被认为是骨肉瘤治疗的有效靶点。因此，GSK3β抑制剂的研究是抗骨肉瘤药物开发中最热门的领域之一。在这里，我们使用生物信息学工具从 ZINC 药物数据库中筛选出新型有效的 GSK3β抑制剂。通过分子对接、分子动力学模拟、MM/GBSA 和能量分解分析来鉴定抑制剂。最后，选择 ZINC08383479 和 ZINC08441251 作为潜在的 GSK3β 抑制剂。通过体外 GSK3β 激酶抑制试验评估这两种抑制剂。在体外通过骨肉瘤细胞系 U2OS 和 MG63 检测细胞增殖抑制作用。结果表明，ZINC08383479 和 ZINC08441251 对 GSK3β 具有高抑制活性。我们发现 CHIR99021（一种已知的 GSK3β 抑制剂）、ZINC08383479 和 ZINC08441251 对 U2OS 细胞和 MG63 细胞均具有显著的抑制活性。这些发现可能为设计更有效的 GSK3β 抑制剂和骨肉瘤治疗靶点提供新的思路。
