相対結合自由エネルギーは,可逆共性阻害剤の選択性を予測できるのか?
Payal Chatterjee1, Wesley M Botello-Smith1, Han Zhang1
1College of Pharmacy, Western University of Health Sciences , Pomona, California 91766, United States.
Journal of the American Chemical Society
|November 11, 2017
まとめ
リバーシブル共性阻害剤は臨床上の利点があるが,その結合親和性を予測することは複雑である. この研究では,同定性結合状態のみを分析することで,選択性を予測することが多いが,同定性のない相互作用も重要であることが示されている.
科学分野:
- コンピュータ化学
- 薬物の発見
- 生物化学
背景:
- リバーシブル共性阻害剤は,他の薬物タイプよりも利点があります.
- 標的の選択性を最適化するには,共振的相互作用と非共振的相互作用の両方を理解する必要があります.
- これらの阻害剤に対する結合親和性を予測することは,多段階の結合プロセスのために困難です.
研究 の 目的:
- 相対的結合自由エネルギーと全体的な可逆共性結合親和の関係を確立する.
- 阻害剤の選択性に対する共性結合状態の予測力を調査する.
- 非共性相互作用が結合親和性および運動性に著しく影響する条件を特定する.
主な方法:
- リバーシブル共電結合を分析するために2つの状態の結合モデルを使用した.
- λ交換分子ダイナミクスを用いた自由エネルギー波動 (FEP).
- カルパイン-1とカルパイン-2に対するα-ケトアミド類の結合自由エネルギー
主要な成果:
- 共同結合状態は,一般的に可逆的共同結合阻害剤の選択性を予測する.
- 非共性結合のステップは,特定の条件下で有意である.
- 同価と非同価の結合状態は,同じ選択性プロファイルを示さない場合があります.
結論:
- 選択性を予測するには,しばしば共性結合状態の分析が十分であるが,非共性貢献も考慮されるべきである.
- FEPとQM/MMの計算を組み合わせると,結合親和性と運動の予測が改善されます.
- 結合状態と運動の両方を調査することは,可逆性共性阻害剤の最適化に不可欠です.
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