Molecular switch controlling the binding of anionic bile acid conjugates to human apical sodium-dependent bile acid transporter.

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Rais R, Acharya C, Tririya G, Mackerell AD, Polli JE

Molecular switch controlling the binding of anionic bile acid conjugates to human apical sodium-dependent bile acid transporter.

J Med Chem. 2010 Jun 24;53(12):4749-60. doi: 10.1021/jm1003683.

PubMed ID

20504026 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Valaciclovir	Ileal sodium/bile acid cotransporter	Protein	Humans	Unknown	Substrate	Details