Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs.
Identification of new EphA4 inhibitors by virtual screening of FDA-approved drugs.
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DOI：
10.1038/s41598-018-25790-1
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发表时间：
2018-05-09
影响因子：
4.6
通讯作者：
Ip NY
中科院分区：
文献类型：
--
作者：
Gu S;Fu WY;Fu AKY;Tong EPS;Ip FCF;Huang X;Ip NY
受体酪氨酸激酶、产生促红细胞生成素的肝细胞 A4 (EphA4) 最近被确定为阿尔茨海默病 (AD) 的分子靶点。我们发现，阻断受体与其配体肝配蛋白的相互作用可以减轻 AD 转基因小鼠模型中的疾病表型，这表明靶向 EphA4 是开发 AD 干预措施的潜在方法。在这项研究中，我们通过使用虚拟筛选与生化和细胞检测相结合的综合方法，确定了五种 FDA 批准的药物——麦角素、赛庚啶、尼罗替尼、阿比特龙和瑞他莫林——作为 EphA4 的潜在抑制剂。我们最初使用针对 EphA4 配体结合域的分子对接筛选了 FDA 批准的药物数据库。然后，我们选择了22种候选药物并检查了它们对EphA4的抑制活性。其中，5种药物可抑制肝配蛋白-A在培养的原代神经元中诱导的EphA4聚集。具体而言，尼罗替尼（一种激酶抑制剂）以剂量依赖性方式在微摩尔水平上抑制 EphA4 和肝配蛋白-A 的结合。此外，尼罗替尼抑制培养的海马神经元中 EphA4 的激活和 EphA4 依赖性生长锥塌陷，表明该药物在细胞环境中表现出 EphA4 抑制活性。正如我们的计算和实验相结合的方法所证明的那样，重新利用 FDA 批准的药物来抑制 EphA4 可能会为识别和开发 AD 新疗法提供一种替代的快速通道方法。
The receptor tyrosine kinase, erythropoietin-producing hepatocellular A4 (EphA4), was recently identified as a molecular target for Alzheimer’s disease (AD). We found that blockade of the interaction of the receptor and its ligands, ephrins, alleviates the disease phenotype in an AD transgenic mouse model, suggesting that targeting EphA4 is a potential approach for developing AD interventions. In this study, we identified five FDA-approved drugs—ergoloid, cyproheptadine, nilotinib, abiraterone, and retapamulin—as potential inhibitors of EphA4 by using an integrated approach combining virtual screening with biochemical and cellular assays. We initially screened a database of FDA-approved drugs using molecular docking against the ligand-binding domain of EphA4. Then, we selected 22 candidate drugs and examined their inhibitory activity towards EphA4. Among them, five drugs inhibited EphA4 clustering induced by ephrin-A in cultured primary neurons. Specifically, nilotinib, a kinase inhibitor, inhibited the binding of EphA4 and ephrin-A at micromolar scale in a dosage-dependent manner. Furthermore, nilotinib inhibited the activation of EphA4 and EphA4-dependent growth cone collapse in cultured hippocampal neurons, demonstrating that the drug exhibits EphA4 inhibitory activity in cellular context. As demonstrated in our combined computational and experimental approaches, repurposing of FDA-approved drugs to inhibit EphA4 may provide an alternative fast-track approach for identifying and developing new treatments for AD.
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