Big Data-Enabled Repurposing of Clopidogrel for Focal Segmental Glomerulosclerosis Using Network Biology

Author:

Perco PaulORCID,Gebeshuber Christoph A.,Ley Matthias,Daniel-Fischer Lisa,Aufricht Christoph,Kratochwill KlausORCID

Abstract

Focal segmental glomerulosclerosis (FSGS) is a rare kidney disease characterized by glomerular lesions and damage to podocytes, terminally differentiated renal cells, that are part of the filtration apparatus in glomeruli. FSGS is often associated with nephrotic syndrome and may lead to end-stage renal failure. FSGS pathophysiology is complex with a number of molecular mechanisms being involved in its development and progression. We used a network-based drug repositioning approach to computationally screen for novel treatment options for FSGS in a systematic way. In brief, we first generated a network-based molecular pathobiology model for FSGS following previously established workflows. FSGS-associated molecular features (i.e., genes and proteins) were mapped onto a human protein–protein dependency network, and network clustering algorithms were used to identify dysregulated FSGS molecular mechanisms and biological processes. Key affected enriched mechanisms included glomerular filtration, cell adhesion and extracellular matrix derangements, inflammation, apoptosis, calcineurin signaling, renin–angiotensin–aldosterone system, and platelet activation as well as dysregulation of fibrinolysis. The network-based FSGS pathobiology model was subsequently used to computationally screen against a library of drug mechanism of action molecular models. The platelet inhibitor clopidogrel was identified as one of the top compounds significantly interfering with FSGS pathophysiology based on in silico graph alignment analysis. Due to its potential to beneficially interfere with key dysregulated molecular FSGS processes, its positive in vivo data in ameliorating renal sclerosis, and its favorable safety profile, clopidogrel appears as an attractive candidate for subsequent evaluation in clinical trials.

Publisher

ScienceOpen

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3