Repurposing FDA-Approved Compounds for the Discovery of Glutaminyl Cyclase Inhibitors as Drugs Against Alzheimer's Disease.
Repurposing FDA-Approved Compounds for the Discovery of Glutaminyl Cyclase Inhibitors as Drugs Against Alzheimer's Disease.
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DOI：
10.1002/open.202000235
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发表时间：
2021-09
期刊：
影响因子：
2.3
通讯作者：
Wu H
中科院分区：
文献类型：
--
作者：
Xu C;Zou H;Yu X;Xie Y;Cai J;Shang Q;Ouyang N;Wang Y;Xu P;He Z;Wu H
阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性痴呆，其病理机制尚不清楚。近年来，寻找能够有效防治AD的疾病调节剂一直是一个挑战。新的证据已经积累，揭示了上调的γ-氨基环化酶（QC）在AD发生中的关键作用。在本研究中，评估了由1621种FDA批准的化合物组成的库的QC抑制效价。共有54个匹配结果（占合并液的3.33%）显示出QC抑制活性。测量具有最高QC抑制活性的前5种化合物的Ki。在这些选定的命中，化合物影响神经元信号传导途径和其他机制的认可。此外，还鉴定了几种具有QC抑制活性的多酚衍生物。分析了这些命中中包含的框架和子集。总之，我们的研究结果可能有助于发现和开发新型QC抑制剂作为潜在的抗AD药物。上调的β-氨基环化酶（QC）在阿尔茨海默病（AD）的发生中起着至关重要的作用。研究了包含1621种FDA批准的化合物的QC抑制效力。建议将这些命中中包含的分子支架和基序（池的3.33%）组合到靶向QC的新片段样文库的设计中。这种方法可以支持开发新型QC抑制剂作为潜在的抗AD药物。
Alzheimer's disease (AD) is one of the most common neurodegenerative causes of dementia, the pathology of which is still not much clear. It′s challenging to discover the disease modifying agents for the prevention and treatment of AD over the years. Emerging evidence has been accumulated to reveal the crucial role of up‐regulated glutaminyl cyclase (QC) in the initiation of AD. In the current study, the QC inhibitory potency of a library consisting of 1621 FDA‐approved compounds was assessed. A total of 54 hits, 3.33 % of the pool, exhibited QC inhibitory activities. The Ki of the top 5 compounds with the highest QC inhibitory activities were measured. Among these selected hits, compounds affecting neuronal signaling pathways and other mechanisms were recognized. Moreover, several polyphenol derivatives with QC inhibitory activities were also identified. Frameworks and subsets contained in these hits were analyzed. Taken together, our results may contribute to the discovery and development of novel QC inhibitors as potential anti‐AD agents. Up‐regulated glutaminyl cyclase (QC) has a crucial role in the initiation of Alzheimer's disease (AD).The QC inhibitory potency of a library containing 1621 FDA‐approved compounds was investigated. Molecule scaffolds and motifs contained in these hits (3.33 % of the pool) are suggested to be combined into the design of new fragment like libraries targeting QC. This approach may support the development of novel QC inhibitors as potential anti‐AD agents.
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作者：
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