title: 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 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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA.
authors.forename: Rana
authors.initials: R
authors.lastname: Rais
authors.forename: Chayan
authors.initials: C
authors.lastname: Acharya
authors.forename: Gasirat
authors.initials: G
authors.lastname: Tririya
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Mackerell
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D000838:Anions; D001647:Bile Acids and Salts / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015999:Multivariate Analysis; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis; D027981:Symporters / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D000814:Aniline Compounds; D000838:Anions; D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter