| Structural determinants for transport across the intestinal bile acid transporter using C-24 bile acid conjugates. | |
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MedLine Citation:
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PMID: 20939504 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The human apical sodium dependent bile acid transporter (hASBT) reabsorbs gram quantities of bile acid daily and is a potential prodrug target to increase oral drug absorption. In the absence of a high resolution hASBT crystal structure, 3D-QSAR modeling may prove beneficial in designing prodrug targets to hASBT. The objective was to derive a conformationally sampled pharmacophore 3D-QSAR (CSP-SAR) model for the uptake of bile acid conjugates by hASBT. A series of bile acid conjugates of glutamyl chenodeoxycholate were evaluated in terms of K(m) and normalized V(max) (normV(max)) using hASBT-MDCK cells. All monoanionic conjugates were potent substrates. Dianions, cations and zwitterions, which bound with a high affinity, were not substrates. CSP-SAR models were derived using structural and physicochemical descriptors, and evaluated via cross validation. The best CSP-SAR model for K(m) included two structural and two physiochemical descriptors, where substrate hydrophobicity enhanced affinity. A best CSP-SAR model for K(m)/normV(max) employed one structural and three physicochemical descriptors, also indicating hydrophobicity enhanced efficiency. Overall, the bile acid C-24 region accommodated a range of substituted anilines, provided a single negative charge was present near C-24. In comparing uptake findings to prior inhibition results, increased hydrophobicity enhanced activity, with dianions and zwitterions hindering activity. |
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Authors:
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Rana Rais; Chayan Acharya; Alexander D Mackerell; James E Polli |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-11-01 |
Journal Detail:
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Title: Molecular pharmaceutics Volume: 7 ISSN: 1543-8392 ISO Abbreviation: Mol. Pharm. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-06 Completed Date: 2011-03-25 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 101197791 Medline TA: Mol Pharm Country: United States |
Other Details:
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Languages: eng Pagination: 2240-54 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, United States. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Cells, Cultured Chenodeoxycholic Acid / analogs & derivatives, chemistry*, pharmacokinetics Computer Simulation Glutamic Acid / chemistry, metabolism, pharmacokinetics Humans Hydrophobic and Hydrophilic Interactions Intestines / chemistry, drug effects, metabolism Kinetics Models, Molecular Molecular Structure Organic Anion Transporters, Sodium-Dependent / antagonists & inhibitors, chemistry*, metabolism Quantitative Structure-Activity Relationship Regression Analysis Stereoisomerism Symporters / antagonists & inhibitors, chemistry*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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DK67530/DK/NIDDK NIH HHS; R01 DK067530-05/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Organic Anion Transporters, Sodium-Dependent; 0/Symporters; 145420-23-1/sodium-bile acid cotransporter; 474-25-9/Chenodeoxycholic Acid; 56-86-0/Glutamic Acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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