Screening serine/threonine and tyrosine kinase inhibitors for histidine kinase inhibition.
Screening serine/threonine and tyrosine kinase inhibitors for histidine kinase inhibition.
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DOI：
10.1016/j.bmc.2018.04.047
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发表时间：
2018-10-15
影响因子：
3.5
通讯作者：
Carlson EE
中科院分区：
文献类型：
--
作者：
Wilke KE;Fihn CA;Carlson EE
细菌双组分系统的组氨酸激酶是有希望的抗菌靶点。尽管它们具有多种多样的作用，但组氨酸激酶超家族中的酶共享可用于同时抑制多种组氨酸激酶的催化核心。以Bergerat折叠为特征，组氨酸激酶ATP结合结构域的特征在丝氨酸/苏氨酸和酪氨酸激酶中没有发现。然而，由于每个激酶家族结合相同的ATP底物，我们试图确定是否已发表的丝氨酸/苏氨酸和酪氨酸激酶抑制剂包含的支架，也将抑制组氨酸激酶。使用选择的测定，从罗氏出版的激酶集的222抑制剂筛选组氨酸激酶的结合，失活和聚集。我们的筛选结果不仅支持不同激酶家族的ATP结合结构域之间的区别，而且所鉴定的先导分子也为进一步开发组氨酸激酶抑制剂提供了灵感。
Histidine kinases of bacterial two-component systems are promising antibacterial targets. Despite their varied, numerous roles, enzymes in the histidine kinase superfamily share a catalytic core that may be exploited to inhibit multiple histidine kinases simultaneously. Characterized by the Bergerat fold, the features of the histidine kinase ATP-binding domain are not found in serine/threonine and tyrosine kinases. However, because each kinase family binds the same ATP substrate, we sought to determine if published serine/threonine and tyrosine kinase inhibitors contained scaffolds that would also inhibit histidine kinases. Using select assays, 222 inhibitors from the Roche Published Kinase Set were screened for binding, deactivation, and aggregation of histidine kinases. Not only do the results of our screen support the distinctions between ATP-binding domains of different kinase families, but the lead molecule identified also presents inspiration for further histidine kinase inhibitor development.
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影响因子：
7.3
作者：
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通讯作者：
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