阐明 PPARG 抑制在增强 MERS 病毒免疫反应中的作用：网络药理学与计算药物发现。

IF 4.7 3区医学 Q1 INFECTIOUS DISEASES

Journal of Infection and Public Health Pub Date : 2024-10-09 DOI:10.1016/j.jiph.2024.102561

Ahmed M. Hassan , Leena H. Bajrai , Azzah S. Alharbi , Meshari M. Alhamdan , Vivek Dhar Dwivedi , Esam I. Azhar

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引用次数: 0

摘要

背景：中东呼吸综合征（MERS）已成为一种严重的人畜共患疾病，由于缺乏特效药物，对公众健康造成了极大的威胁。这迫切需要开发新型治疗分子。了解 MERS 的遗传基础和潜在治疗靶点对于开发有效的治疗方法至关重要：方法：利用 GEO2R 分析了两个基因表达数据集（GSE81909 和 GSE100504），以确定差异表达基因（DEGs）。此外，还进行了基因本体（GO）、通路富集分析和蛋白-蛋白相互作用（PPI）网络分析，以了解基因的功能。研究人员确定了一个可能的药物靶点，并利用分子对接技术针对选定的靶点筛选了一个经 FDA 批准的药物库，并通过分子动力学模拟、主成分分析、自由能图谱和 MM/GBSA 计算验证了研究结果：对 GSE81909 和 GSE100504 数据集上的 icMERS 和 MOCK 样本进行 24 小时和 48 小时的研究发现，分别有 73 个和 267 个 DEGs 上调。在网络药理学中，STAT1、MX1、DDX58、EIF2AK2、ISG15、IFIT1、IFIH1、OAS1、IRF9 和 OASL 被确定为十大枢纽基因。STAT1 被确定为这 10 大枢纽基因中关联度最高的枢纽基因，它在对 MERS 病毒的免疫反应中起着至关重要的作用。对 STAT1 的进一步研究表明，PPARG 有助于减少 STAT1，从而调节免疫反应。因此，通过抑制 PPARG，可以成功增强免疫反应。已知的 PPARG 抑制剂 570（Farglitazar）被用作对照。此外，还使用 Tanimoto 和 K-mean 聚类方法进行了筛选，从中确定了三种化合物：2267、3478 和 40326。化合物 3478 显示出与对照组相似的特征，表明与 PPARG 的结合力很强。3478 的负结合自由能最高，为 -41.20 kcal/mol，表明与 PPARG 的结合力很强：这些研究结果表明，3478有望成为一种潜在的PPARG抑制剂，进一步的实验研究可以探索其作为MERS抑制剂的潜力。

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Elucidating the role of PPARG inhibition in enhancing MERS virus immune response: A network pharmacology and computational drug discovery

Background

Middle East Respiratory Syndrome (MERS) has become a severe zoonotic disease, posing significant public health concerns due to the lack of specific medications. This urgently demands the development of novel therapeutic molecules. Understanding MERS's genetic underpinnings and potential therapeutic targets is crucial for developing effective treatments.

Methods

Two gene expression datasets (GSE81909 and GSE100504) were analyzed to identify differentially expressed genes (DEGs) using GEO2R. Furthermore, gene ontology (GO), pathway enrichment analysis, and protein-protein interaction (PPI) network were performed to understand the gene’s functions. A possible drug target was identified, and an FDA-approved drug library was screened against the selected target using molecular docking and validated the findings through molecular dynamics simulation, principal component analysis, free energy landscape, and MM/GBSA calculations.

Results

The study on GSE81909 and GSE100504 datasets with icMERS and MOCK samples at 24 and 48 h revealed an upregulation in 73 and 267 DEGs, respectively. In the network pharmacology, STAT1, MX1, DDX58, EIF2AK2, ISG15, IFIT1, IFIH1, OAS1, IRF9, and OASL were identified as the top 10 hub genes. STAT1 was identified as the most connected hub gene among these top 10 hub genes, which plays a crucial role in the immune response to the MERS virus. Further study on STAT1 showed that PPARG helps reduce STAT1, which could modulate the immune response. Therefore, by inhibiting PPARG, the immunological response can be successfully enhanced. The known inhibitor of PPARG, 570 (Farglitazar), was used as a control. Further, screening using Tanimoto and K-mean clustering was performed, from which three compounds were identified: 2267, 3478, and 40326. Compound 3478 showed characteristics similar to the control, indicating robust binding to PPARG. 3478 showed the highest negative binding free energy with −41.20 kcal/mol, indicating strong binding with PPARG.

Conclusions

These findings suggest that 3478 promises to be a potential inhibitor of PPARG, and further experimental investigations can explore its potential as a MERS inhibitor.

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来源期刊

Journal of Infection and Public Health PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH -INFECTIOUS DISEASES

CiteScore

13.10

自引率

1.50%

发文量

203

审稿时长

96 days

期刊介绍： The Journal of Infection and Public Health, first official journal of the Saudi Arabian Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences and the Saudi Association for Public Health, aims to be the foremost scientific, peer-reviewed journal encompassing infection prevention and control, microbiology, infectious diseases, public health and the application of healthcare epidemiology to the evaluation of health outcomes. The point of view of the journal is that infection and public health are closely intertwined and that advances in one area will have positive consequences on the other. The journal will be useful to all health professionals who are partners in the management of patients with communicable diseases, keeping them up to date. The journal is proud to have an international and diverse editorial board that will assist and facilitate the publication of articles that reflect a global view on infection control and public health, as well as emphasizing our focus on supporting the needs of public health practitioners. It is our aim to improve healthcare by reducing risk of infection and related adverse outcomes by critical review, selection, and dissemination of new and relevant information in the field of infection control, public health and infectious diseases in all healthcare settings and the community.