转录组
生物信息学
计算生物学
安普克
药物重新定位
基因
药品
生物
体内
药物开发
生物信息学
基因表达
遗传学
药理学
磷酸化
蛋白激酶A
作者
Xu Chi,Daosheng Ai,Dawei Shi,Shengbao Suo,Xingwei Chen,Yizhen Yan,Yaqiang Cao,Rui Zhang,Na Sun,Weizhong Chen,Joseph McDermott,Shiqiang Zhang,Yingying Zeng,Jing‐Dong J. Han
出处
期刊:Cell Reports
[Cell Press]
日期:2018-10-01
卷期号:25 (2): 523-535.e5
被引量:27
标识
DOI:10.1016/j.celrep.2018.09.031
摘要
Experimental large-scale screens for drug repositioning are limited by restriction to in vitro conditions and lack of applicability to real human conditions. Here, we developed an in silico screen in human in vivo conditions using a reference of single gene mutations' non-tissue-specific "core transcriptome signatures" (CSs) of 8,476 genes generated from the TCGA database. We developed the core-signature drug-to-gene (csD2G) software to scan 3,546 drug treatment profiles against the reference signatures. csD2G significantly outperformed conventional cell line-based gene perturbation signatures and existing drug-repositioning methods in both coverage and specificity. We highlight this with 3 demonstrated applications: (1) repositioned category of psychiatric drugs to inhibit the TGF-β pathway; (2) antihypertensive calcium channel blockers predicted to activate AMPK and inhibit AKT pathways, and validated by clinical electronic medical records; and (3) 7 drugs predicted and validated to selectively target the AKT-FOXO and AMPK pathways and thus regulate worm lifespan.
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