Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases.
Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases.
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DOI：
10.1021/acs.jmedchem.7b01066
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发表时间：
2017-10-12
影响因子：
7.3
通讯作者：
Carlson EE
中科院分区：
文献类型：
--
作者：
Goswami M;Wilke KE;Carlson EE
细菌组氨酸激酶（HK）是广泛存在于细菌中的典型调节酶。除了它们的调节作用外，它们还参与毒力因子的产生并赋予病原微生物对各种抗生素的抗性。我们以前曾报道过通过靶向保守的催化和ATP结合（CA）结构域来抑制多个HK的化合物。在此，我们进行了详细的结构-活性关系的腺嘌呤为基础的抑制剂，使用生物化学和对接方法评估。这些研究得出了若干意见。首先，抑制剂的胺基与保守活性位点Asp的相互作用对于活性至关重要，并且可能决定其在结合口袋中的方向。第二，抑制剂支架中的N-NH-N三联体对于结合保守的Gly：Asp：Asn残基是高度优选的。最后，在腺嘌呤核心的几个位置上的疏水吸电子基团增强了效力。这些抑制剂的选择性进行了测试对热休克蛋白90（HSP 90），它具有类似的ATP结合倍。我们发现靶向催化结构域的ATP-盖部分的基团，例如六元环，赋予HK选择性。
Bacterial histidine kinases (HKs) are quintessential regulatory enzymes found ubiquitously in bacteria. Apart from their regulatory roles, they are also involved in the production of virulence factors and conferring resistance to various antibiotics in pathogenic microbes. We have previously reported compounds that inhibit multiple HKs by targeting the conserved catalytic and ATP-binding (CA) domain. Herein, we conduct a detailed structure–activity relationship assessment of adenine-based inhibitors using biochemical and docking methods. These studies have resulted in several observations. First, interaction of an inhibitor’s amine group with the conserved active-site Asp is essential for activity and likely dictates its orientation in the binding pocket. Second, a N-NH-N triad in the inhibitor scaffold is highly preferred for binding to conserved Gly:Asp:Asn residues. Lastly, hydrophobic electron-withdrawing groups at several positions in the adenine core enhance potency. The selectivity of these inhibitors was tested against heat shock protein 90 (HSP90), which possesses a similar ATP-binding fold. We found that groups that target the ATP-lid portion of the catalytic domain, such as a six-membered ring, confer selectivity for HKs.
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