基于人工智能与全球上市药物数据探寻抗垂体腺瘤药物及体外实验验证  

Screening anti-pituitary adenoma drugs from global marketed drug data based on artificial intelligence and validating with in vitro experiments

作　　者：吕婷婷 张子睿 李尚 孙岚[1] 杜冠华[1] LYU Tingting;ZHANG Zirui;LI Shang;SUN Lan;DU Guanhua(Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China)

机构地区：[1]中国医学科学院北京协和医学院药物研究所药物筛选中心,北京100050

出　　处：《江苏大学学报（医学版）》2022年第3期185-193,共9页Journal of Jiangsu University：Medicine Edition

基　　金：国家自然科学基金面上项目(82070056,81670456);重大新药创制科技重大专项(2018ZX09711001-003-011,2018ZX09711001-012)。

摘　　要：目的:基于人工智能技术与药物重定位策略从上市药物中探寻潜在的垂体腺瘤治疗药物。方法:通过基因表达数据库(Gene Expression Omnibus,GEO)分析垂体腺瘤的基因表达谱,从中筛选出评分最高的Hub基因;利用药物重定位策略从全球上市药物数据库中找到靶向Hub基因的治疗药物,并通过人工智能技术验证药物与靶点的相互作用。细胞实验中,CCK8法检测他莫昔芬对小鼠垂体腺瘤AtT-20细胞和大鼠垂体腺瘤GH3细胞增殖能力的影响,流式细胞术检测细胞凋亡率,蛋白质印迹法检测磷脂酰肌醇3-激酶(phosphatidylinositol-3-kinase,PI3K)蛋白激酶B(protein kinase B,AKT)凋亡通路中关键蛋白的表达。结果:在巨腺瘤与微腺瘤中鉴定出96个差异表达基因,其中评分最高的基因是信号转导与转录激活因子6(signal transducer and activator of transcription 6,STAT6),从数据库中重定位找到靶向STAT6的治疗药物是他莫昔芬;联合人工智能技术及分子对接确证他莫昔芬与靶点STAT6相互作用。体外实验结果表明他莫昔芬对垂体腺瘤细胞增殖及激素分泌具有抑制作用。结论:他莫昔芬能抑制垂体腺瘤生长,为垂体腺瘤的靶点研究及精准治疗提供了有力证据。Objective:Exploring potential treatment drugs for pituitary adenoma from marketed drugs based on artificial intelligence technology and drug relocation strategies.Methods:The gene expression profile of pituitary adenoma was analyzed by Gene Expression Omnibus(GEO)database,and the highest scoring Hub gene was screened out.The drug repositioning strategy was used to find therapeutic drugs targeting Hub gene from the global market drug database,and the interaction between drug and target was validated by artificial intelligence technology.In cell experiments,the effect of tamoxifen on the proliferation ability of mouse pituitary adenoma AtT-20 cells and rat pituitary adenoma GH3 cells was detected by CCK8 method,the apoptosis rate was detected by flow cytometry,and the expressions of key proteins in the phosphatidylinositol-3-kinase(PI3K)-protein kinase B(AKT)apoptosis pathway was detected by Western blotting.Results:A total of 96 differentially expressed genes were identified from macroadenomas and microadenomas,among which signal transducer and activator of transcription 6(STAT6)was the gene with the highest score.Tamoxifen was found to be the therapeutic drug targeting STAT6 by relocating from the database.The interaction between tamoxifen and STAT6 was confirmed by artificial intelligence and molecular docking.Finally,in vitro experiments showed that tamoxifen could inhibit the proliferation of pituitary adenoma cells and hormone secretion.Conclusion:Tamoxifen can inhibit the growth of pituitary adenoma,providing strong evidence for the target research and precise treatment of pituitary adenoma.

关 键 词：垂体腺瘤 人工智能 药物重定位 信号转导与转录激活因子6 他莫昔芬 

分 类 号：R736.4[医药卫生—肿瘤]