Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP).
Structure-activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate cotransporting polypeptide (NTCP).
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DOI：
10.1021/mp300453k
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发表时间：
2013-03-04
影响因子：
4.9
通讯作者：
Polli JE
中科院分区：
文献类型：
--
作者：
Dong Z;Ekins S;Polli JE
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’s 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.
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影响因子：
4.6
作者：
Kolhatkar, Vidula;Polli, James E.
通讯作者：
Polli, James E.
影响因子：
5.1
作者：
Campbell, SD;de Morais, SM;Xu, JHJ
通讯作者：
Xu, JHJ
影响因子：
3.7
作者：
Balakrishnan, A;Sussman, DJ;Polli, JE
通讯作者：
Polli, JE
影响因子：
1.8
作者：
Choi, Min-Koo;Shin, Ho Jung;Song, Im-Sook
通讯作者：
Song, Im-Sook
影响因子：
3.7
作者：
Kolhatkar, Vidula;Polli, James E.
通讯作者：
Polli, James E.