エレクトロフィール・フラグメント・スクリーニングによるコヴァレンツ・プローブ・ディスカバリー
Efrat Resnick, Anthony Bradley1,2, Jinrui Gan
1Department of Chemistry , Chemistry Research Laboratory , 12 Mansfield Road , Oxford OX1 3TA , U.K.
Journal of the American Chemical Society
|May 8, 2019
まとめ
強力な共性探査機を 発見することは困難です この研究では,OTUB2やNUDT7のようなこれまで対象外だった酵素を選択的に検知する新しい電離断片スクリーニング方法が導入されました.
科学分野:
- 化学生物学
- 薬物の発見
- フラグメントベースのスクリーニング
背景:
- コヴァレンスの探査機は,優れた効能と持続時間を提供しますが,発見することは困難です.
- 電子的な断片は強力ですが 選択性が欠けていることが多いです
- 以前の断片スクリーニング方法は,可逆結合物質の低親和によって制限されています.
研究 の 目的:
- 選択的共性リンガンドを発見するための実用的で効率的な方法を開発する.
- 電子的な断片に伴う選択性の課題を克服するためです.
- 挑戦的なタンパク質の標的を特定する.
主な方法:
- 軽度な電離性断片の993人のメンバーのライブラリの構築と特徴付け.
- 断片の特徴化のための高通量チオール反応性測定法の開発.
- 図書館をシステインを含む10のタンパク質に対してスクリーニングし,その後に高通量結晶学を行う.
主要な成果:
- 軽い電ophilesは選択的であることが証明され,非常に反応的な断片は稀である.
- スクリーニングアプローチは,テストされたタンパク質の標的のほとんどがヒットしました.
- OTUB2 と NUDT7 に対して強力で選択的な共性プローブが急速に開発されました.
結論:
- エレクトロフィール断片スクリーニングは,共振性リガンド発見のための実行可能で効率的な戦略です.
- 軽い電ophilesは,標的の選択性を達成するために成功裏に使用することができます.
- このアプローチは,酵素標的のための新しい共性探査機の迅速な識別を可能にします.
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