σ2受容体の構造は,生物活性リガンド発見のためのドッキングを可能にします
Assaf Alon1, Jiankun Lyu2, Joao M Braz3
1Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Nature
|December 9, 2021
まとめ
研究者は,構造ベースのスクリーニングを使用して新しいシグマ2受容体リガンドを発見しました. これらの強力で選択的な化合物は 神経疾患の痛みやその他の生物学的過程の研究に 有望な結果を示しています
科学分野:
- 薬理学と構造生物学
- 神経科学
背景:
- シグマ2受容体は,がんのイメージング,精神疾患,神経疾患の痛みの主要な標的である.
- シグマ2受容体の相互作用を理解することは,標的治療の開発に不可欠である.
研究 の 目的:
- シグマ2受容体の結晶構造を既知のリガンドと複合的に決定する.
- 新しい化学型を特定するために,これらの構造を大規模な仮想スクリーニングに使用する.
- 神経病痛におけるシグマ2受容体の役割を調査する.
主な方法:
- ロルペリドンとPB28でシグマ2受容体の結晶構造の決定
- 4億9千万の化合物の 仮想スクリーニング
- 484の化合物の合成と親和性試験
- 効能と選択性のためのヒット化合物の最適化
- ニューロパシー疼痛のマウスモデルにおける in vivo 効果試験
主要な成果:
- アフィニティ > 1 μM の新しい化学型127種が特定され,そのうちの31種はアフィニティ > 50 nM であった.
- シグマ1受容体より250倍以上の選択性を有する3つの化合物を最適化しました.
- 強力なシグマ2リガンドが神経疾患の痛みモデルにおける機械的過敏症を軽減することを示した.
- シグマ2受容体に結合した2つのリガンドの共結晶構造を通してドッキングされたポーズが確認されました.
結論:
- 構造ベースのスクリーニングにより,超大型のライブラリで in vivo 探査機を素早く発見できます.
- シグマ2受容体は, nociceptionにおいて重要な役割を果たしています.
- このアプローチは未知の生物学的標的の研究を容易にする.
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