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

Rana Rais, Chayan Acharya, Gasirat Tririya, Alexander D. MacKerell, James E. Polli

Research output: Contribution to journalArticle

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 conjugates 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.

Original languageEnglish (US)
Pages (from-to)4749-4760
Number of pages12
JournalJournal of medicinal chemistry
Volume53
Issue number12
DOIs
StatePublished - Jun 24 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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