Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2)

J Med Chem. 2008 Jun 12;51(11):3275-87. doi: 10.1021/jm7015683. Epub 2008 May 6.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / toxicity
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / toxicity
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Antiviral Agents / toxicity
  • Biological Transport / drug effects
  • Cell Line
  • Computer Simulation
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug-Related Side Effects and Adverse Reactions*
  • Estradiol / analogs & derivatives
  • Estradiol / metabolism
  • Humans
  • Insecta
  • Liver / drug effects
  • Liver / metabolism
  • Models, Molecular
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
  • Multidrug Resistance-Associated Proteins / biosynthesis
  • Multidrug Resistance-Associated Proteins / genetics
  • Neoplasm Proteins / antagonists & inhibitors
  • Pharmaceutical Preparations / chemistry*
  • Pharmacology*
  • Structure-Activity Relationship

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Antipsychotic Agents
  • Antiviral Agents
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Pharmaceutical Preparations
  • estradiol-17 beta-glucuronide
  • multidrug resistance-associated protein 2
  • Estradiol
  • Cytochrome P-450 Enzyme System