Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering & Pharmacy, Wuhan Institute of Technology, Wuhan 430073, PR China.
Eur J Med Chem. 2010 Sep;45(9):3595-600. doi: 10.1016/j.ejmech.2010.05.004. Epub 2010 May 12.
A series of novel enaminone amides with improved side effect were synthesized by Hogenkamp et al. To explore the action mechanisms of enaminone amides, the homology model of rat alpha1beta2gamma2 GABAR was generated using the cryo-electron microscopy structure of the nAChR of Torpedo marmorata and the AChBP of Lymnaea stagnalis as the templates. Molecular docking and pharmacophore analyses allowed us to speculate the critical residues involving to the recognition of the ligands. The docking results indicated His128, Tyr186 and Tyr236 of alpha subunit were essential to form H-bond interactions contacts with the ligands. Specially, the N-substituents of enaminone amides as the sterically favored areas could form the important hydrophobic interactions with the residue Tyr186.
霍根坎普等人合成了一系列具有改善副作用的新型烯胺酰胺。为了探索烯胺酰胺的作用机制，使用美洲电鳗烟碱型乙酰胆碱受体和淡水蜗牛 AChBP 的冷冻电镜结构作为模板，生成了大鼠α1β2γ2GABAR 的同源模型。分子对接和药效团分析使我们能够推测涉及配体识别的关键残基。对接结果表明，α亚基的 His128、Tyr186 和 Tyr236 对于与配体形成氢键相互作用至关重要。特别是，烯胺酰胺的 N-取代基作为空间有利区域，可以与残基 Tyr186 形成重要的疏水相互作用。
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