In this study, we demonstrate that our modified Gene Set Enrichment Analysis (GSEA) method, drug perturbation GSEA (dpGSEA), can detect phenotypically relevant drug targets through a unique transcriptomic enrichment that emphasizes biological directionality of drug-derived gene sets. We detail our dpGSEA method and show its effectiveness in detecting specific perturbation of drugs in independent public datasets by confirming fluvastatin, paclitaxel, and rosiglitazone perturbation in gastroenteropancreatic neuroendocrine tumor cells. In drug discovery experiments, we found that dpGSEA was able to detect phenotypically relevant drug targets in previously published differentially expressed genes of CD4+T regulatory cells from immune responders and non-responders to antiviral therapy in HIV-infected individuals, such as those involved with virion replication, cell cycle dysfunction, and mitochondrial dysfunction. dpGSEA is publicly available at https://github.com/sxf296/drug_targeting . dpGSEA is an approach that uniquely enriches on drug-defined gene sets while considering directionality of gene modulation. We recommend dpGSEA as an exploratory tool to screen for possible drug targeting molecules.

中文翻译：

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药物扰动基因集富集分析（dpGSEA）：一种新的转录组药物筛选方法

在这项研究中，我们证明了我们改进的基因集富集分析 (GSEA) 方法，药物扰动 GSEA (dpGSEA)，可以通过强调药物衍生基因集的生物方向性的独特转录组富集来检测表型相关的药物靶点。我们详细介绍了我们的 dpGSEA 方法，并通过确认胃肠胰腺神经内分泌肿瘤细胞中的氟伐他汀、紫杉醇和罗格列酮的扰动，展示了其在独立公共数据集中检测药物特定扰动的有效性。在药物发现实验中，我们发现 dpGSEA 能够在先前发表的 CD4+T 调节细胞差异表达基因中检测表型相关的药物靶标，这些基因来自免疫应答者和对 HIV 感染者的抗病毒治疗无应答者，例如与病毒粒子复制、细胞周期功能障碍和线粒体功能障碍有关的那些。dpGSEA 可在 https://github.com/sxf296/drug_targeting 公开获得。dpGSEA 是一种独特富集药物定义基因集的方法，同时考虑基因调控的方向性。我们推荐将 dpGSEA 作为一种探索性工具来筛选可能的药物靶向分子。