化学
药效团
羧酸盐
立体化学
配体(生物化学)
分子模型
胆汁酸
结合
取代基
戒指(化学)
氢键
分子内力
运输机
数量结构-活动关系
组合化学
分子
生物化学
有机化学
受体
数学分析
基因
数学
作者
Rana Rais,Chayan Acharya,Gasirat Tririya,Alexander D. MacKerell,James E. Polli
摘要
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.
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