title: Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP).
abstract: 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.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , 20 Penn Street, Baltimore, Maryland 21201, USA.
authors: Zhongqi
authors: Z
authors: Dong
authors: Sean
authors: S
authors: Ekins
authors: James E
authors: JE
authors: Polli
mesh_terms: D001384:Azetidines / Q000737:chemistry / Q000494:pharmacology; D001499:Bayes Theorem; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D019295:Computational Biology; D000069438:Ezetimibe; D006801:Humans; D000077405:Irbesartan; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D001384:Azetidines; D001713:Biphenyl Compounds; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D013777:Tetrazoles; C071908:sodium-bile acid cotransporter; D000069438:Ezetimibe; D000077405:Irbesartan