Document Detail

Structural determinants for transport across the intestinal bile acid transporter using C-24 bile acid conjugates.
MedLine Citation:
PMID:  20939504     Owner:  NLM     Status:  MEDLINE    
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.
Rana Rais; Chayan Acharya; Alexander D Mackerell; James E Polli
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-11-01
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  7     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-06     Completed Date:  2011-03-25     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2240-54     Citation Subset:  IM    
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, United States.
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MeSH Terms
Cells, Cultured
Chenodeoxycholic Acid / analogs & derivatives,  chemistry*,  pharmacokinetics
Computer Simulation
Glutamic Acid / chemistry,  metabolism,  pharmacokinetics
Hydrophobic and Hydrophilic Interactions
Intestines / chemistry,  drug effects,  metabolism
Models, Molecular
Molecular Structure
Organic Anion Transporters, Sodium-Dependent / antagonists & inhibitors,  chemistry*,  metabolism
Quantitative Structure-Activity Relationship
Regression Analysis
Symporters / antagonists & inhibitors,  chemistry*,  metabolism
Grant Support
Reg. No./Substance:
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

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