シルカディアンリズムを調節するメラトニン受容体のリガンドの仮想発見
Reed M Stein1, Hye Jin Kang2, John D McCorvy2,3
1Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Nature
|February 11, 2020
まとめ
研究者は数百万個の分子をスクリーニングすることによって,新しいMT1選択逆アゴニストを発見しました. これらの化合物は マウスの昼夜リズムを効果的にリセットし 睡眠や気分障害の治療に 新たな可能性を秘めています
科学分野:
- 神経科学
- 薬理学について
- クロノバイオロジー
背景:
- メラトニンはMT1とMT2受容体を通して昼夜リズムを同期します.
- MT1とMT2受容体は睡眠障害とうつ病の標的である.
- in vivoで有効なMT1選択リガンドの限られた利用は,研究と薬の開発を妨げています.
研究 の 目的:
- 新しい,in vivoで活性なMT1選択リガンドを特定する.
- メラトニン受容体生物学を調節するための新しい化学型を探求する.
- サーカディアンリズムに関する理解を深めるため
主な方法:
- MT1の結晶構造に対して 1億5千万個以上の分子の仮想スクリーニング
- 高級ドッキングされた化合物の構造ベースの最適化.
- シルカディアン再訓練のマウスモデルで合成されたリガンドの体内試験.
主要な成果:
- 強力なMT1選択逆アゴニスト (470 pMから6 μM) の発見
- トポロジ的に関連のない化学型の識別
- MT1選択逆アゴニストによるマウスの昼間時計 (1. 3 - 1.5 h) の相進出が実証された.
結論:
- 大型ライブラリの構造ベースのスクリーニングは,新しい,in vivoの活性リガンドを生成することができます.
- MT1選択逆アゴニストは,昼夜リズム調節のための有望な道を示しています.
- これらの発見は,昼夜リズム障害の標的治療の開発に新しい可能性をもたらします.
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