title: Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2).
abstract: The chemical space of registered oral drugs was explored for inhibitors of the human multidrug-resistance associated protein 2 (MRP2; ABCC2), using a data set of 191 structurally diverse drugs and drug-like compounds. The data set included a new reference set of 75 compounds, for studies of hepatic drug interactions with transport proteins, CYP enzymes, and compounds associated with liver toxicity. The inhibition of MRP2-mediated transport of estradiol-17beta-D-glucuronide was studied in inverted membrane vesicles from Sf9 cells overexpressing human MRP2. A total of 27 previously unknown MRP2 inhibitors were identified, and the results indicate an overlapping but narrower inhibitor space for MRP2 compared with the two other major ABC efflux transporters P-gp (ABCB1) and BCRP (ABCG2). In addition, 13 compounds were shown to stimulate the transport of estradiol-17beta-D-glucuronide. The experimental results were used to develop a computational model able to discriminate inhibitors from noninhibitors according to their molecular structure, resulting in a predictive power of 86% for the training set and 72% for the test set. The inhibitors were in general larger and more lipophilic and presented a higher aromaticity than the noninhibitors. The developed computational model is applicable in an early stage of the drug discovery process and is proposed as a tool for prediction of MRP2-mediated hepatic drug interactions and toxicity.
authors.affiliation: Pharmaceutical Screening and Informatics, Department of Pharmacy, Uppsala University, Biomedical Center, Uppsala, Sweden.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Pedersen
authors.forename: Pär
authors.initials: P
authors.lastname: Matsson
authors.forename: Christel A S
authors.initials: CA
authors.lastname: Bergström
authors.forename: Ulf
authors.initials: U
authors.lastname: Norinder
authors.forename: Janet
authors.initials: J
authors.lastname: Hoogstraate
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007313:Insecta; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010600:Pharmacology; D013329:Structure-Activity Relationship
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D014150:Antipsychotic Agents; D000998:Antiviral Agents; D003577:Cytochrome P-450 Enzyme System; D004958:Estradiol; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D004364:Pharmaceutical Preparations; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C025483:estradiol-17 beta-glucuronide