探索以基因、蛋白质和途径为重点的治疗范例，以对抗麻风病和结核病：网络医学和药物再利用方法

IF 4.7 3区医学 Q1 INFECTIOUS DISEASES

Journal of Infection and Public Health Pub Date : 2025-03-19 DOI:10.1016/j.jiph.2025.102763

Mohd Imran , Ahmed S. Alshrari , Mariah N. Hafiz , Mohammed M. Jawad , Abida Khan , Fadiyah Jadid Alanazi , Syed Mohammed Basheeruddin Asdaq

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引用次数: 0

摘要

麻风和结核病分别由麻风分枝杆菌和结核分枝杆菌引起，是具有重大公共卫生影响的慢性感染。虽然麻风病影响皮肤和周围神经，而结核病主要针对肺部，但这两种疾病都涉及全身免疫反应。本研究结合转录组学分析、化学信息学和分子动力学模拟来确定分子机制和潜在的治疗靶点。方法对转录组学数据集进行分析，确定异常基因和通路。途径富集组织特异性和大量RNA-seq表达分析提供了生物学背景。系统生物学网络揭示了调控中心基因，分子对接研究评估了CHEMBL化合物作为潜在治疗药物的潜力。分子动力学（MD）模拟通过RMSD RMSF和MM-GBSA自由能计算来评估顶部配体-蛋白复合物的稳定性。结果基因表达分析鉴定出HSP90AA1、MAPK8IP3、ZMPSTE24等13个核心异常基因。组织特异性表达关键基因定位于肺组织和免疫细胞，HSP90AA1在肺泡巨噬细胞和上皮细胞中高表达。HSP90AA1基因作为一个中心枢纽基因参与了96个相互作用的应激反应途径。对接研究发现，CHEMBL3653862和CHEMBL3653884与Asp93和Tyr139具有很强的结合亲和力（-10.16至−12.69 kcal/mol）。MD模拟证实了结合稳定性，RMSD波动在2.1-3.5 Å范围内，MM-GBSA能量值支持配体-蛋白质的稳定性。结论本研究确定HSP90AA1是麻风和结核病的潜在药物靶点。研究结果支持宿主导向的治疗方法，并强调了计算建模在加速药物发现中的重要性。该研究为未来的实验验证奠定了基础，包括体外和体内测试，以推进这些慢性感染的药物再利用策略。

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Exploring therapeutic paradigm focusing on genes, proteins, and pathways to combat leprosy and tuberculosis: A network medicine and drug repurposing approach

Background

Leprosy and tuberculosis caused by Mycobacterium leprae and Mycobacterium tuberculosis, respectively, are chronic infections with significant public health implications. While leprosy affects the skin and peripheral nerves and tuberculosis primarily targets the lungs, both diseases involve systemic immune responses. This study integrates transcriptomic analysis cheminformatics and molecular dynamics simulations to identify molecular mechanisms and potential therapeutic targets.

Methods

Transcriptomic datasets were analyzed to identify dysregulated genes and pathways. Pathway enrichment tissue-specific and bulk RNA-seq expression analyses provided biological context. System biology networks revealed regulatory hub genes and molecular docking studies evaluated CHEMBL compounds as potential therapeutics. Molecular dynamics (MD) simulations assessed the stability of top ligand-protein complexes through RMSD RMSF and MM-GBSA free energy calculations.

Results

Gene expression analysis identified 13 core dysregulated genes, including HSP90AA1 MAPK8IP3 and ZMPSTE24. Tissue-specific expression localized pivotal genes to lung tissues and immune cells with HSP90AA1 highly expressed in alveolar macrophages and epithelial cells. HSP90AA1 gene emerged as a central hub gene with 96 interactions involved in stress response pathways. Docking studies identified CHEMBL3653862 and CHEMBL3653884 with strong binding affinities (-10.16 to −12.69 kcal/mol) interacting with Asp93 and Tyr139. MD simulations confirmed binding stability with RMSD fluctuations within 2.1–3.5 Å and MM-GBSA energy values supporting ligand-protein stability.

Conclusion

This study identifies HSP90AA1 as a potential drug target in leprosy and tuberculosis. Findings support host-directed therapy approaches and highlight the importance of computational modeling in accelerating drug discovery. The study provides a foundation for future experimental validation, including in vitro and in vivo testing to advance drug repurposing strategies for these chronic infections.

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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.