Systems and Synthetic Biology Lab, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (NA) 80078, Italy.
Institute for Research in Biomedicine (IRB Barcelona), C/ Baldiri Reixac 10, 08028 Barcelona, Spain.
Bioinformatics. 2018 May 1;34(9):1498-1505. doi: 10.1093/bioinformatics/btx800.
Drug repositioning has been proposed as an effective shortcut to drug discovery. The availability of large collections of transcriptional responses to drugs enables computational approaches to drug repositioning directly based on measured molecular effects.
We introduce a novel computational methodology for rational drug repositioning, which exploits the transcriptional responses following treatment with small molecule. Specifically, given a therapeutic target gene, a prioritization of potential effective drugs is obtained by assessing their impact on the transcription of genes in the pathway(s) including the target. We performed in silico validation and comparison with a state-of-art technique based on similar principles. We next performed experimental validation in two different real-case drug repositioning scenarios: (i) upregulation of the glutamate-pyruvate transaminase (GPT), which has been shown to induce reduction of oxalate levels in a mouse model of primary hyperoxaluria, and (ii) activation of the transcription factor TFEB, a master regulator of lysosomal biogenesis and autophagy, whose modulation may be beneficial in neurodegenerative disorders.
A web tool for Gene2drug is freely available at http://gene2drug.tigem.it. An R package is under development and can be obtained from https://github.com/franapoli/gep2pep.
Supplementary data are available at Bioinformatics online.
药物重定位被提议为药物发现的有效捷径。大量的药物转录反应数据集使基于测量的分子效应的药物重定位计算方法成为可能。
我们引入了一种新的药物重定位计算方法，该方法利用小分子处理后的转录反应。具体来说，给定一个治疗靶基因，通过评估其对包括靶基因在内的通路中基因转录的影响，来获得潜在有效药物的优先级。我们进行了计算机模拟验证，并与基于类似原理的最新技术进行了比较。接下来，我们在两种不同的实际药物重定位场景中进行了实验验证：(i)谷氨酸-丙酮酸转氨酶 (GPT) 的上调，已在原发性高草酸尿症的小鼠模型中显示可诱导草酸盐水平降低，(ii) 转录因子 TFEB 的激活，该因子是溶酶体生物发生和自噬的主调控因子，其调节可能有益于神经退行性疾病。
Gene2drug 的网络工具可在 http://gene2drug.tigem.it 免费获得。一个 R 包正在开发中，并可从 https://github.com/franapoli/gep2pep 获得。
补充数据可在生物信息学在线获得。
