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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / antagonists & inhibitors
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Administration, Oral
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / toxicity
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Antipsychotic Agents / chemistry
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Antipsychotic Agents / pharmacology
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Antipsychotic Agents / toxicity
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Antiviral Agents / toxicity
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Biological Transport / drug effects
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Cell Line
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Computer Simulation
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Cytochrome P-450 Enzyme System / metabolism
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Drug-Related Side Effects and Adverse Reactions*
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Estradiol / analogs & derivatives
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Estradiol / metabolism
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Humans
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Insecta
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Liver / drug effects
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Liver / metabolism
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Models, Molecular
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
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Multidrug Resistance-Associated Proteins / biosynthesis
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Multidrug Resistance-Associated Proteins / genetics
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Neoplasm Proteins / antagonists & inhibitors
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Pharmaceutical Preparations / chemistry*
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Pharmacology*
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Structure-Activity Relationship
Substances
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ABCB1 protein, human
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ABCC2 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Antineoplastic Agents
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Antipsychotic Agents
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Antiviral Agents
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins
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Neoplasm Proteins
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Pharmaceutical Preparations
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estradiol-17 beta-glucuronide
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Estradiol
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Cytochrome P-450 Enzyme System