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Molecular Pharmacology

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Research ArticleArticle

Structure-Based Identification of OATP1B1/3 Inhibitors

Tom De Bruyn, Gerard J. P. van Westen, Adriaan P. IJzerman, Bruno Stieger, Peter de Witte, Patrick F. Augustijns and Pieter P. Annaert
Molecular Pharmacology June 2013, 83 (6) 1257-1267; DOI: https://doi.org/10.1124/mol.112.084152
Tom De Bruyn
Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (T.D.B., P.F.A., P.P.A.); Division of Medical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands (G.J.P.V.W., A.P.I.); Department of Clinical Pharmacology and Toxicology, University Hospital, Zürich, Switzerland (B.S.); and Laboratory for Molecular Biodiscovery, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (P.D.W.)
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Gerard J. P. van Westen
Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (T.D.B., P.F.A., P.P.A.); Division of Medical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands (G.J.P.V.W., A.P.I.); Department of Clinical Pharmacology and Toxicology, University Hospital, Zürich, Switzerland (B.S.); and Laboratory for Molecular Biodiscovery, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (P.D.W.)
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Adriaan P. IJzerman
Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (T.D.B., P.F.A., P.P.A.); Division of Medical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands (G.J.P.V.W., A.P.I.); Department of Clinical Pharmacology and Toxicology, University Hospital, Zürich, Switzerland (B.S.); and Laboratory for Molecular Biodiscovery, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (P.D.W.)
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Bruno Stieger
Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (T.D.B., P.F.A., P.P.A.); Division of Medical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands (G.J.P.V.W., A.P.I.); Department of Clinical Pharmacology and Toxicology, University Hospital, Zürich, Switzerland (B.S.); and Laboratory for Molecular Biodiscovery, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (P.D.W.)
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Peter de Witte
Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (T.D.B., P.F.A., P.P.A.); Division of Medical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands (G.J.P.V.W., A.P.I.); Department of Clinical Pharmacology and Toxicology, University Hospital, Zürich, Switzerland (B.S.); and Laboratory for Molecular Biodiscovery, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (P.D.W.)
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Patrick F. Augustijns
Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (T.D.B., P.F.A., P.P.A.); Division of Medical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands (G.J.P.V.W., A.P.I.); Department of Clinical Pharmacology and Toxicology, University Hospital, Zürich, Switzerland (B.S.); and Laboratory for Molecular Biodiscovery, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (P.D.W.)
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Pieter P. Annaert
Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (T.D.B., P.F.A., P.P.A.); Division of Medical Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands (G.J.P.V.W., A.P.I.); Department of Clinical Pharmacology and Toxicology, University Hospital, Zürich, Switzerland (B.S.); and Laboratory for Molecular Biodiscovery, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium (P.D.W.)
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Abstract

Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.

Footnotes

    • Received December 9, 2012.
    • Accepted April 8, 2013.
  • This study was supported by grants from “Fonds voor Wetenschappelijk Onderzoek,” Flanders [G.0662.09N] and “Onderzoeksfonds” of the KU Leuven, Belgium.

    T.D.B. received a Ph.D. scholarship [093306] from the Agency for Innovation by Science and Technology, Flanders; G.V.W. received funding from Tibotec BVBA.

  • dx.doi.org/10.1124/mol.112.084152.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (6)
Molecular Pharmacology
Vol. 83, Issue 6
1 Jun 2013
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Research ArticleArticle

Structure-Based Identification of OATP1B Inhibitors

Tom De Bruyn, Gerard J. P. van Westen, Adriaan P. IJzerman, Bruno Stieger, Peter de Witte, Patrick F. Augustijns and Pieter P. Annaert
Molecular Pharmacology June 1, 2013, 83 (6) 1257-1267; DOI: https://doi.org/10.1124/mol.112.084152

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Research ArticleArticle

Structure-Based Identification of OATP1B Inhibitors

Tom De Bruyn, Gerard J. P. van Westen, Adriaan P. IJzerman, Bruno Stieger, Peter de Witte, Patrick F. Augustijns and Pieter P. Annaert
Molecular Pharmacology June 1, 2013, 83 (6) 1257-1267; DOI: https://doi.org/10.1124/mol.112.084152
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