Molecular Switch Controlling the Binding of Anionic Bile Acid Conjugates to Human Apical Sodium-Dependent Bile Acid Transporter
Molecular Switch Controlling the Binding of Anionic Bile Acid Conjugates to Human Apical Sodium-Dependent Bile Acid Transporter
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DOI：
10.1021/jm1003683
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发表时间：
2010-06-24
影响因子：
7.3
通讯作者：
Polli, James E.
中科院分区：
文献类型：
--
作者：
Rais, Rana;Acharya, Chayan;Polli, James E.
人顶端钠依赖性胆汁酸转运蛋白（hASBT）可以作为口服药物吸收的前药靶点。合成、生物、NMR 和计算方法确定了单阴离子胆汁酸缀合物和双阴离子胆汁酸缀合物与 hASBT 结合的结构活性关系。实验数据与构象采样药效团/QSAR 建模方法 (CSP-SAR) 相结合，预测胆烷骨架上的羟基与缀合物芳香环上的酸基之间具有分子内氢键的双阴离子取代基会增加缀合物的疏水性并改善结合亲和力。值得注意的是，该模型预测了构象分子开关的存在，其中通过单个位置控制的结合亲和力来移动芳环上的羧酸取代基。通过在芳香环附近插入亚甲基，有效地改变羧酸盐的空间位置来进行模型验证，从而导致预测的结合亲和力的变化。这项工作说明了构象是配体理化性质和配体与生物转运蛋白结合亲和力的决定因素。
The human apical sodium-dependent bile acid transporter (hASBT) may serve as a prodrug target for oral drug absorption. Synthetic, biological, NMR, and computational approaches identified the structure activity relationships of mono- and dianionic bile acid conjugates for hASBT binding. Experimental data combined with a conformationally sampled pharmacophore/QSAR modeling approach (CSP-SAR) predicted that dianionic substituents with intramolecular hydrogen bonding between hydroxyls on the cholane skeleton and the acid group on the conjugate's aromatic ring increased conjugate hydrophobicity and improved binding affinity. Notably, the model predicted the presence of a conformational molecular switch, where shifting the carboxylate substituent on an aromatic ring by a single position controlled binding affinity. Model validation was performed by effectively shifting the spatial location of the carboxylate by inserting a methylene adjacent to the aromatic ring, resulting in the predicted alteration in binding affinity. This work illustrates conformation as a determinant of ligand physiochemical properties and ligand binding affinity to a biological transporter.