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首页> 美国卫生研究院文献>Computational and Structural Biotechnology Journal >Computational Drug Screening Identifies Compounds Targeting Renal Age-associated Molecular Profiles
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Computational Drug Screening Identifies Compounds Targeting Renal Age-associated Molecular Profiles

机译：计算药物筛选可鉴定靶向肾脏年龄相关分子谱的化合物

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Aging is a major driver for chronic kidney disease (CKD) and the counterbalancing of aging processes holds promise to positively impact disease development and progression.In this study we generated a signature of renal age-associated genes (RAAGs) based on six different data sources including transcriptomics data as well as data extracted from scientific literature and dedicated databases. Protein abundance in renal tissue of the 634 identified RAAGs was studied next to the analysis of affected molecular pathways. RAAG expression profiles were furthermore analysed in a cohort of 63 CKD patients with available follow-up data to determine association with CKD progression. 23 RAAGs were identified showing concordant regulation in renal aging and CKD progression. This set was used as input to computationally screen for compounds with the potential of reversing the RAAG/CKD signature on the transcriptional level. Among the top-ranked drugs we identified atorvastatin, captopril, valsartan, and rosiglitazone, which are widely used in clinical practice for the treatment of patients with renal and cardiovascular diseases. Their positive impact on the RAAG/CKD signature could be validated in an in-vitro model of renal aging.In summary, we have (i) consolidated a set of RAAGs, (ii) determined a subset of RAAGs with concordant regulation in CKD progression, and (iii) identified a set of compounds capable of reversing the proposed RAAG/CKD signature.
机译：衰老是慢性肾脏病（CKD）的主要驱动力，而衰老过程的平衡有望正面影响疾病的发展和进程。在这项研究中，我们基于六个不同的数据来源生成了与肾脏衰老相关的基因（RAAG）的特征。包括转录组学数据以及从科学文献和专用数据库中提取的数据。在分析受影响的分子途径之后，对634种已鉴定的RAAGs的肾组织中的蛋白质丰度进行了研究。进一步分析了63例CKD患者的RAAG表达谱，并提供了随访数据，以确定与CKD进展的相关性。鉴定出23个RAAG，它们在肾脏衰老和CKD进程中显示出一致的调节作用。该集合用作输入，以计算筛选具有在转录水平上逆转RAAG / CKD签名的潜力的化合物。在排名最高的药物中，我们确定了阿托伐他汀，卡托普利，缬沙坦和罗格列酮，它们在临床实践中广泛用于治疗肾脏和心血管疾病患者。可以在体外肾衰老模型中验证它们对RAAG / CKD信号的积极影响。总之，我们（i）合并了一组RAAG，（ii）确定了在CKD进程中具有一致调节作用的RAAG子集（iii）确定了一组能够逆转建议的RAAG / CKD签名的化合物。

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