ArticleJournal of medicinal chemistry2010
Molecular switch controlling the binding of anionic bile acid conjugates to human apical sodium-dependent bile acid transporter.
Article in Journal of medicinal chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 23 citations in OpenAlex.
- Computer-Aided Drug Design Methods.Methods in molecular biology (Clifton, N.J.) · 2017Article
- A substrate pharmacophore for the human sodium taurocholate co-transporting polypeptide.International journal of pharmaceutics · 2015Article
- Mechanistic interpretation of conventional Michaelis-Menten parameters in a transporter system.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2014Article
- An updated review on drug-induced cholestasis: mechanisms and investigation of physicochemical properties and pharmacokinetic parameters.Journal of pharmaceutical sciences · 2013Review
- Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions.Pharmaceutical research · 2013Article
- Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP).Molecular pharmaceutics · 2013Article
- Automation of the CHARMM General Force Field (CGenFF) I: bond perception and atom typing.Journal of chemical information and modeling · 2012Article
- Deconstructing 14-phenylpropyloxymetopon: minimal requirements for binding to mu opioid receptors.Bioorganic & medicinal chemistry · 2012Article
- Intrinsic energy landscapes of amino acid side-chains.Journal of chemical information and modeling · 2012Article
- Structural requirements of bile acid transporters: C-3 and C-7 modifications of steroidal hydroxyl groups.European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · 2012Article
- Consensus 3D model of μ-opioid receptor ligand efficacy based on a quantitative Conformationally Sampled Pharmacophore.The journal of physical chemistry. B · 2011Article
- Computational ligand-based rational design: Role of conformational sampling and force fields in model development.MedChemComm · 2011Article
- Structural determinants for transport across the intestinal bile acid transporter using C-24 bile acid conjugates.Molecular pharmaceutics · 2010Article
- Reliability of inhibition models to correctly identify type of inhibition.Pharmaceutical research · 2010Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
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.
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