title: A substrate pharmacophore for the human sodium taurocholate co-transporting polypeptide.
abstract: Human sodium taurocholate co-transporting polypeptide (NTCP) is the main bile acid uptake transporter in the liver with the capability to translocate xenobiotics. While its inhibitor requirements have been recently characterized, its substrate requirements have not. The objectives of this study were (a) to elucidate NTCP substrate requirements using native bile acids and bile acid analogs, (b) to develop the first pharmacophore for NTCP substrates and compare it with the inhibitor pharmacophores, and (c) to identify additional NTCP novel substrates. Thus, 18 native bile acids and two bile acid conjugates were initially assessed for NTCP inhibition and/or uptake, which suggested a role of hydroxyl pattern and steric interaction in NTCP binding and translocation. A common feature pharmacophore for NTCP substrate uptake was developed, using 14 native bile acids and bile acid conjugates, yielding a model which featured three hydrophobes, one hydrogen bond donor, one negative ionizable feature and three excluded volumes. This model was used to search a database of FDA approved drugs and retrieved the majority of the known NTCP substrates. Among the retrieved drugs, irbesartan and losartan were identified as novel NTCP substrates, suggesting a potential role of NTCP in drug disposition.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA.
authors.forename: Zhongqi
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay Varina, NC 27526, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Ekins
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, Baltimore, Maryland 21201, USA. Electronic address: jpolli@rx.umaryland.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D000077405:Irbesartan; D019808:Losartan / Q000494:pharmacology*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors / Q000378:metabolism*; D027981:Symporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001647:Bile Acids and Salts; D001713:Biphenyl Compounds; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D013777:Tetrazoles; C071908:sodium-bile acid cotransporter; D000077405:Irbesartan; D019808:Losartan
keywords: Bile acids; Irbesartan; Losartan; Pharmacophore; Sodium taurocholate co-transporting polypeptide (NTCP); Transporters