Identification of lead anti-human cytomegalovirus compounds targeting MAP4K4 via machine learning analysis of kinase inhibitor screening data.
Identification of lead anti-human cytomegalovirus compounds targeting MAP4K4 via machine learning analysis of kinase inhibitor screening data.
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DOI：
10.1371/journal.pone.0201321
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Al-Ali H
中科院分区：
文献类型：
--
作者：
Strang BL;Asquith CRM;Moshrif HF;Ho CM;Zuercher WJ;Al-Ali H
涉及高度注释的化合物集和基于细胞的高通量筛选的化学基因组学方法正在成为鉴定新药物靶点的手段。我们先前已经筛选了一系列高度表征的激酶抑制剂（Khan等人，Journal of General Virology，2016）以鉴定增加或减少感染细胞中人巨细胞病毒（HCMV）蛋白表达的化合物。为了鉴定潜在的新型抗HCMV药物靶标，我们使用机器学习方法将来自上述筛选的表型数据与该筛选中使用的化合物的激酶抑制谱相关联。一些潜在的目标没有以前报道的作用，HCMV复制。我们专注于一个潜在的抗HCMV靶点MAPK 4K，并鉴定了抑制MAP 4K 4的先导化合物，其具有抗HCMV活性，细胞毒性很小。我们发现，用MAP 4K 4抑制剂或抑制MAP 4K 4产生的siRNA处理HCMV感染的细胞，减少HCMV复制并损害IE 2 -60的检测，IE 2 -60是HCMV有效复制所必需的病毒蛋白。我们的研究结果证明了这种机器学习方法在识别新型抗病毒药物靶标方面的潜力，这可以为发现新型抗病毒先导化合物提供信息。
Chemogenomic approaches involving highly annotated compound sets and cell based high throughput screening are emerging as a means to identify novel drug targets. We have previously screened a collection of highly characterized kinase inhibitors (Khan et al., Journal of General Virology, 2016) to identify compounds that increase or decrease expression of a human cytomegalovirus (HCMV) protein in infected cells. To identify potential novel anti-HCMV drug targets we used a machine learning approach to relate our phenotypic data from the aforementioned screen to kinase inhibition profiling of compounds used in this screen. Several of the potential targets had no previously reported role in HCMV replication. We focused on one potential anti-HCMV target, MAPK4K, and identified lead compounds inhibiting MAP4K4 that have anti-HCMV activity with little cellular cytotoxicity. We found that treatment of HCMV infected cells with inhibitors of MAP4K4, or an siRNA that inhibited MAP4K4 production, reduced HCMV replication and impaired detection of IE2-60, a viral protein necessary for efficient HCMV replication. Our findings demonstrate the potential of this machine learning approach to identify novel anti-viral drug targets, which can inform the discovery of novel anti-viral lead compounds.
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影响因子：
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作者：
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发表时间：
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