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

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 control

SUBMITTER: Rais R 

PROVIDER: S-EPMC2891776 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature