基于疾病基因表达谱和药物转录组的抗高尿酸血症药物“重定位”  

“Relocalization”of anti-hyperuricemia drugs based on disease gene expression Profile and Drug transcriptome

作　　者：逄成章 刘文彬 金小宝 PANG Chengzhang;LIU Wenbin;JIN Xiaobao(School of Life Sciences and Biopharmaceutics,Guangdong Pharmaceutical University,Guangzhou 510006,China)

机构地区：[1]广东药科大学生命科学与生物制药学院,广州510006 [2]广东省生物活性药物研究重点实验室,广州511436

出　　处：《实用医学杂志》2022年第22期2838-2844,共7页The Journal of Practical Medicine

基　　金：广东省医学科学技术研究基金资助项目(编号:A2022069);广东省中医药局中医药科研基金资助项目(编号:20232086)。

摘　　要：目的采用疾病基因表达谱和药物转录组相结合的老药新用策略,从老药中筛选具有抗高尿酸血症的药物。方法通过高尿酸血症(hyperuricemia,HUA)转录组数据库筛选HUA差异表达基因,使用DAVID数据库与STRING平台对差异基因进行筛选与分析。通过Connectivity Map数据库从候选药物中筛选预测抗HUA药物,选择富集分数较高的药物与差异表达核心靶点,利用SwissDock平台进行分子对接。CCK-8法检测候选抗HUA药物对HK-2细胞活力的影响,验证候选药物对HUA细胞模型的黄嘌呤氧化酶活性和尿酸浓度的影响。结果在HUA转录组数据库中,获得1492个差异基因,其中下调基因810个,上调基因682个,差异基因涉及HDASC deacetylate histones、IL-7、UB-specific processing proteases等通路;通过Connectivity Map数据库预测15个药物具有抗HUA潜力,分子对接表明阿维菌素与核心靶点IL-1β、TNF、CXCL2和IL-6的结合能分别为-7.68、-7.97、-6.25、-6.73 kcal/mol;细胞实验表明,12.5~100μg/mL药物浓度范围内阿维菌素具有良好的细胞安全性、抑制黄嘌呤氧化酶活性和降低尿酸作用(P<0.05)。结论通过疾病基因表达谱和药物转录组数据相结合策略发现阿维菌素具有抗高尿酸潜力。Objective Drugs with anti-hyperuricemia were screened from old drugs by the strategy of new use of old drugs based on disease gene expression profile and drug transcriptome.Methods Hyperuricemia(HUA)transcriptome database was used to screen hyperuricemia differentially expressed genes,and the DAVID database and STRING platform were used to screen and analyze the differentially expressed genes.The predicted anti-HUA drugs were screened from the old drugs by the Connectivity Map database,the drugs with high enrichment fractions were selected and differentially expressed core targets,and the SwissDock platform was used for molecular docking.The CCK-8 assay was used to detect the effect of candidate anti-HUA drugs on HK-2 cell viability,and to verify the effect of candidate drugs on xanthine oxidase activity and uric acid concentration in the HUA cell model.Results In the HUA transcriptome database,1492 differential genes were obtained,including 810 downregulated genes and 682 up-regulated genes.The differential genes involved HDASC deacetylate histones,IL-7,UB-specific processing proteases,and other pathways.The 15 drugs were predicted to have anti-HUA potential by the Connectivity Map database.Molecular docking showed that the binding energies of avermectin to the core targets IL-1β,TNF,CXCL2,and IL-6 were-7.68,-7.97,-6.25,and-6.73 kcal/mol,respectively.The results of cell experiments showed that avermectin had good cell safety,inhibited xanthine oxidase activity,and reduced uric acid in the concentration range of 12.5~100μg/mL.Conclusions This present study found that the old drug abamectin has anti-hyperuric acid potential through a combination of disease gene expression profile and drug transcriptome data.

关 键 词：阿维菌素 疾病基因表达谱 药物转录组 高尿酸血症 分子对接 

分 类 号：R589.7[医药卫生—内分泌]