Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH
Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH
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DOI：
10.1073/pnas.1007140107
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发表时间：
2010-07-27
影响因子：
11.1
通讯作者：
Dougherty, Dennis A.
中科院分区：
文献类型：
--
作者：
Blum, Angela P.;Lester, Henry A.;Dougherty, Dennis A.
烟碱激动剂的药效团模型已经提出了四十年。这些模型的核心是阳离子氮和氢键受体的存在。现在已经确定，阳离子中心与保守的色氨酸产生重要的阳离子-π相互作用，但是所提出的氢键受体的供体更难识别。结合到乙酰胆碱结合蛋白的尼古丁结构预测药效团的第二组分的结合伴侣是水分子，其也与受体的互补亚基的主链氢键结合。在这里，我们使用非天然氨基酸诱变加上激动剂类似物，以检查是否这样的氢键是功能上显着的α 4 β 2神经元乙酰胆碱受体，受体与尼古丁成瘾。我们发现了与激动剂尼古丁、乙酰胆碱、氨甲酰胆碱和地棘蛙素形成氢键的证据。这些数据代表了一个完整的烟碱药效团，并提供了深入了解选择性靶向这些受体的新的治疗药物的设计。
Pharmacophore models for nicotinic agonists have been proposed for four decades. Central to these models is the presence of a cationic nitrogen and a hydrogen bond acceptor. It is now well-established that the cationic center makes an important cation-pi interaction to a conserved tryptophan, but the donor to the proposed hydrogen bond acceptor has been more challenging to identify. A structure of nicotine bound to the acetylcholine binding protein predicted that the binding partner of the pharmacophore's second component was a water molecule, which also hydrogen bonds to the backbone of the complementary subunit of the receptors. Here we use unnatural amino acid mutagenesis coupled with agonist analogs to examine whether such a hydrogen bond is functionally significant in the alpha 4 beta 2 neuronal nAChR, the receptor most associated with nicotine addiction. We find evidence for the hydrogen bond with the agonists nicotine, acetylcholine, carbamylcholine, and epibatidine. These data represent a completed nicotinic pharmacophore and offer insight into the design of new therapeutic agents that selectively target these receptors.