Document Detail

Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP).
MedLine Citation:
PMID:  23339484     Owner:  NLM     Status:  MEDLINE    
The hepatic bile acid uptake transporter sodium taurocholate cotransporting polypeptide (NTCP) is less well characterized than its ileal paralog, the apical sodium dependent bile acid transporter (ASBT), in terms of drug inhibition requirements. The objectives of this study were (a) to identify FDA approved drugs that inhibit human NTCP, (b) to develop pharmacophore and Bayesian computational models for NTCP inhibition, and (c) to compare NTCP and ASBT transport inhibition requirements. A series of NTCP inhibition studies were performed using FDA approved drugs, in concert with iterative computational model development. Screening studies identified 27 drugs as novel NTCP inhibitors, including irbesartan (Ki = 11.9 μM) and ezetimibe (Ki = 25.0 μM). The common feature pharmacophore indicated that two hydrophobes and one hydrogen bond acceptor were important for inhibition of NTCP. From 72 drugs screened in vitro, a total of 31 drugs inhibited NTCP, while 51 drugs (i.e., more than half) inhibited ASBT. Hence, while there was inhibitor overlap, ASBT unexpectedly was more permissive to drug inhibition than was NTCP, and this may be related to NTCP possessing fewer pharmacophore features. Findings reflected that a combination of computational and in vitro approaches enriched the understanding of these poorly characterized transporters and yielded additional chemical probes for possible drug-transporter interaction determinations.
Zhongqi Dong; Sean Ekins; James E Polli
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S.     Date:  2013-02-12
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  10     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-04     Completed Date:  2013-09-04     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1008-19     Citation Subset:  IM    
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MeSH Terms
Azetidines / chemistry,  pharmacology
Bayes Theorem
Biphenyl Compounds / chemistry,  pharmacology
Computational Biology
Organic Anion Transporters, Sodium-Dependent / antagonists & inhibitors*
Structure-Activity Relationship
Symporters / antagonists & inhibitors*
Tetrazoles / chemistry,  pharmacology
United States
United States Food and Drug Administration
Grant Support
Reg. No./Substance:
0/Azetidines; 0/Biphenyl Compounds; 0/Organic Anion Transporters, Sodium-Dependent; 0/Symporters; 0/Tetrazoles; 138402-11-6/irbesartan; 145420-23-1/sodium-bile acid cotransporter; 163222-33-1/ezetimibe

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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