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Identification, K i determination and CoMFA analysis of nuclear receptor ligands as competitive inhibitors of OATP1B1‐mediated estradiol‐17β‐glucuronide transport
Author(s) -
Gui Chunshan,
Wahlgren Brett,
Lushington Gerald H.,
Hagenbuch Bruno
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.748.3
Subject(s) - chemistry , organic anion transporting polypeptide , nuclear receptor , transporter , drug , receptor , binding site , xenobiotic , non competitive inhibition , pregnane x receptor , biochemistry , substrate (aquarium) , ligand (biochemistry) , drug discovery , stereochemistry , pharmacology , transcription factor , enzyme , biology , gene , ecology
Evidence shows that drug‐drug interactions can occur at the level of drug transporters such as the organic anion transporting polypeptide (OATP) 1B1, which mediates uptake of amphipathic organic compounds from blood into hepatocytes. Nuclear receptors are ligand‐activated transcription factors that play an important role in xenobiotic disposition and human diseases. Several of these nuclear receptor ligands have been shown to interact with OATP1B1. To understand the mechanisms of the polyspecificity of OATP1B1 and to predict and prevent the adverse drug‐drug interactions knowledge of a high‐resolution structure is critical. Because there is no crystal structure of Oatps/OATPs available to date, we attempted to elucidate the characteristics of the substrate binding site of OATP1B1 based on interactions with small molecules. First, we identified inhibitors of the model substrate estradiol‐17β‐glucuronide of OATP1B1 from about 40 nuclear receptor ligands. Then, we performed inhibition kinetic studies to identify competitive inhibitors and determine their K i values which ranged from submicromolar to submillimolar. Finally, we performed CoMFA analysis on the identified competitive inhibitors. The CoMFA results indicate that the substrate binding site of OATP1B1 consists of a large hydrophobic middle part with basic residues at both ends that could be very important for substrate binding.