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CH/π相互作用を利用したPKCδ選択的薬剤の創製

利用 CH/π 相互作用创建 PKCδ 选择性药物

基本信息

批准号：
17035046
负责人：
入江一浩
金额：
$ 1.54万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2005
资助国家：
日本
起止时间：
2005 至无数据
项目状态：
已结题

项目摘要

発がんプロモーターの主要なターゲットであるプロテインキナーゼC(PKC)には、10種のアイソザイムが存在する。放線菌の産生するindolactam-V(1)は、nMオーダーでPKC C1ドメインに結合する。一方、1のインドール環をベンゼン環に置換したbenzolactam-V8(2)は、1と同じ水素結合性官能基を有しているにも関わらず、1よりも約30倍低い結合活性しか示さない。本研究代表者らは、1とPKCδのC1ドメイン(δ-C1B)との結合において、インドール環とδ-C1Bの11番目のプロリン残基(Pro-11)がCH/π相互作用(水素原子とπ電子系との間の引力的相互作用)することにより結合能が高められている可能性に注目した。フッ素原子は、水素原子とファンデルワールス半径が最も近い一方で、CH/π相互作用をほとんどしない。そこで、δ-C1BのPro-11の4位水素原子2個をフッ素原子に置換した変異ペプチドを合成し、1および2との結合能を評価した。その結果、1の変異ペプチドに対する結合能は、野生型に比べて11.5倍低下したのに対し、2では結合能の低下が認められなかった。これより、2のPKC結合活性が1よりも低い理由が、CH/π相互作用の欠如に由来すること、また、1のインドール環は、Pro-11の4位水素原子とCH/π相互作用することによって、1の高いPKC結合活性に寄与していることが示唆された。Pro-11は、全PKCアイソザイムC1ドメインに保存されていることから、リガンドの適当な位置に芳香環を結合させることによって、PKC結合活性を高めることができるはずである。このような観点から2の9,10位にベンゼン環を結合させたnaphtholactam-V8をデザインした。本化合物は、2よりも約10倍強いPKCδ結合活性を示した。

There are 10 kinds of PKC products in the market, which are the most important ones. The combination of indolactam-V (1) and nM (1) was confirmed by the combination of bacteria and PKC C1. On the one hand, the environmental protection environment is equipped with benzolactam-V8 (2), 1 is combined with water and water, the functional basis is sensitive, and the activity is about 30 times lower than that of the other. In this study, the representative of this study is the combination of PKC δ C1 (δ-C1B) and δ-C1B (δ-C1B). In this study, the representative of this study, the representative of this study, is the representative of this study, the representative of this study is the combination of δ-C1B (δ-C1B) and δ-C1B (δ-C1B). In this study, the representative of this study, the representative of this study, the combination of δ-C1B, δ-C1B and δ-C1B. The radii of water atoms and water atoms are the closest to each other, and the CH/ π interactions are similar to each other. The 4-position water atoms of δ-C1B and δ-C1B were synthesized by the combination of two atoms, one and two atoms, and the other two atoms were synthesized by the combination of two atoms. The results showed that the binding energy of wild type was 11.5 times lower than that of wild type, and that of wild type was 11.5 times lower than that of wild type, and that of wild type was 11.5 times lower than that of wild type. The reasons for low temperature, 2-PKC binding activity, CH/-π interaction, and CH/-π interaction of 4 water atoms, such as CH/-π interaction, and PKC-binding activity, respectively, show that the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water atoms in the environment, the interaction between the four water Pro-11, full-PKC, full-size, high-temperature, high-temperature, high-performance, high-temperature, high-temperature, high- In the second half of the year, 10 people will be invited to join the environment of the local naphtholactam-V8 in Beijing. The binding activity of this compound is about 10 times stronger than that of PKC δ.