標的型共性キナーゼ阻害剤の設計のためのライシンとシステインの反応性の評価
Ruibin Liu1, Zhi Yue1, Cheng-Chieh Tsai1
1Department of Pharmaceutical Sciences , School of Pharmacy, University of Maryland , Baltimore , Maryland 21201 , United States.
Journal of the American Chemical Society
|April 5, 2019
まとめ
リスインを標的とした共性阻害剤は システインベースの薬を超えて 薬剤耐性などの制限に対処する新しい戦略を提供します この研究では,反応性ライシンをキナーゼで特定し,合理的な共性阻害剤の発見を加速しました.
科学分野:
- 生物化学
- 薬剤化学
- コンピュータ生物学
背景:
- 標的型共性阻害剤の設計はますます重要になってきている.
- システイン標的化は一般的だが,少量の量と耐性によって制限されている.
- リスインを標的にした探査機はリスインの反応性を探求する.
研究 の 目的:
- ヒトキナーゼにおける核愛性 (反応性) 触媒性ライシンの有病率を調査する.
- 選択的,ライシン標的の共性キナーゼ阻害剤の設計のための新しい戦略を開発する.
- 反応性残留物を特定するための新しいpKa予測ツールの可能性を評価する.
主な方法:
- 連続的な定数pHの分子動態に基づいたpKa予測ツールを使用した.
- ヒトのキノームの結晶構造を分析した
- 特定のキナーゼ構造 (DFG-out/αC-out) のリジン反応性を遡及的に予測した.
主要な成果:
- 触媒性リンジンは特定のキナーゼ構造で核愛性であると予測された.
- 他の反応性ライシンとシステインは,様々なキナーゼの位置で特定されました.
- リスインとシステインは,生理学的pHで中性および電荷状態に存在し,現在の計算仮定に異議を唱えます.
結論:
- 選択的ライシン標的共性キナーゼ阻害剤を設計するための新しい戦略を提唱し,II型可逆阻害剤を改変した.
- 開発されたpKa予測ツールは,共性抑制剤の合理的な発見を加速することができます.
- リジンとシステインのプロトネーション状態に関する発見は,計算式キナーゼの研究を変化させる可能性があります.
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