二酰基甘油（DAG）的构象受限类似物。25. 对sn-1和sn-2羰基官能团的研究揭示了脂质界面处sn-1羰基在DAG内酯与蛋白激酶C结合中的重要作用。
Conformationally constrained analogues of diacylglycerol (DAG). 25. Exploration of the sn-1 and sn-2 carbonyl functionality reveals the essential role of the sn-1 carbonyl at the lipid interface in the binding of DAG-lactones to protein kinase C.
作者信息
Kang Ji-Hye, Peach Megan L, Pu Yongmei, Lewin Nancy E, Nicklaus Marc C, Blumberg Peter M, Marquez Victor E
机构信息
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
出版信息
J Med Chem. 2005 Sep 8;48(18):5738-48. doi: 10.1021/jm050352m.
Abstract
Diacylglycerol (DAG) lactones with altered functionality (C=O --> CH(2) or C=O --> C=S) at the sn-1 and sn-2 carbonyl pharmacophores were synthesized and used as probes to dissect the individual role of each carbonyl in the binding to protein kinase C (PKC). The results suggest that the hydrated sn-1 carbonyl is engaged in very strong hydrogen-bonding interactions with the charged lipid headgroups and organized water molecules at the lipid interface. Conversely, the sn-2 carbonyl has a more modest contribution to the binding process as a result of its involvement with the receptor (C1 domain) via conventional hydrogen bonding to the protein. The parent DAG-lactones, E-6 and Z-7, were designed to bind exclusively in the sn-2 binding mode to ensure the correct orientation and disposition of pharmacophores at the binding site.
摘要
合成了在sn-1和sn-2羰基药效基团处具有功能改变（C=O → CH(2)或C=O → C=S）的二酰甘油（DAG）内酯，并将其用作探针来剖析每个羰基在与蛋白激酶C（PKC）结合中的单独作用。结果表明，水合的sn-1羰基与带电荷的脂质头部基团以及脂质界面处有序排列的水分子存在非常强的氢键相互作用。相反，sn-2羰基由于通过与蛋白质的常规氢键作用参与受体（C1结构域）的结合，因此对结合过程的贡献较小。母体DAG内酯E-6和Z-7被设计为仅以sn-2结合模式结合，以确保药效基团在结合位点的正确取向和布局。
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