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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Molecular Determinants of Ligand Selectivity for the Human Multidrug and Toxin Extruder Proteins MATE1 and MATE2-K

Bethzaida Astorga, Sean Ekins, Mark Morales and Stephen H. Wright
Journal of Pharmacology and Experimental Therapeutics June 2012, 341 (3) 743-755; DOI: https://doi.org/10.1124/jpet.112.191577
Bethzaida Astorga
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Sean Ekins
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Mark Morales
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Stephen H. Wright
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Abstract

The present study compared the selectivity of two homologous transport proteins, multidrug and toxin extruders 1 and 2-K (MATE1 and MATE2-K), and developed three-dimensional pharmacophores for inhibitory ligand interaction with human MATE1 (hMATE1). The human orthologs of MATE1 and MATE2-K were stably expressed in Chinese hamster ovary cells, and transport function was determined by measuring uptake of the prototypic organic cation (OC) substrate 1-methyl-4-phenylpyridinium (MPP). Both MATEs had similar apparent affinities for MPP, with Ktapp values of 4.4 and 3.7 μM for MATE1 and MATE2-K, respectively. Selectivity was assessed for both transporters from IC50 values for 59 structurally diverse compounds. Whereas the two transporters discriminated markedly between a few of the test compounds, the IC50 values for MATE1 and MATE2-K were within a factor of 3 for most of them. For hMATE1 there was little or no correlation between IC50 values and the individual molecular descriptors LogP, total polar surface area, or pKa. The IC50 values were used to generate a common-features pharmacophore, quantitative pharmacophores for hMATE1, and a Bayesian model suggesting molecular features favoring and not favoring the interaction of ligands with hMATE1. The models identified hydrophobic regions, hydrogen bond donor and hydrogen bond acceptor sites, and an ionizable (cationic) feature as key determinants for ligand binding to MATE1. In summary, using a combined in vitro and computational approach, MATE1 and MATE2-K were found to have markedly overlapping selectivities for a broad range of cationic compounds, including representatives from seven novel drug classes of Food and Drug Administration-approved drugs.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant 1R01DK080801; National Research Service Award DK752422]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant 5P30ES006694]; and the National Institutes of Health National Heart, Lung, and Blood Institute [Grant 5T32HL07249].

  • S.E. consults for Collaborative Drug Discovery, Inc.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.191577.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    OC
    organic cation
    OCT
    OC transporter
    MATE
    multidrug and toxin extruder
    hMATE
    human MATE
    RPT
    renal proximal tubule
    MPP
    1-methyl-4-phenylpyridinium
    FDA
    Food and Drug Administration
    CHO
    Chinese hamster ovary
    FRT
    Flp recombination target
    WB
    Waymouth buffer
    DMSO
    dimethyl sulfoxide
    IVIS
    in vitro/in silico
    ASP
    4–4-dimethlaminostyryl)-N-methyl-pyridinium
    PYR
    pyrimethamine
    PYR-2
    (5-(4-chlorophenyl)-6-ethyl-2,4-pyrimidinediamine):1-(2-chlorophenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
    PYR-3
    1-(3-chlorophenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
    APMI
    azidoprocainamide
    TPSA
    topological polar surface area
    3D
    three-dimensional
    TEA
    tetraethylammonium
    TPeA
    tetrapentylammonium
    CAESAR
    Conformer Algorithm based on Energy Screening and Recursive Buildup.

  • Received January 5, 2012.
  • Accepted March 13, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 341 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 341, Issue 3
1 Jun 2012
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Selectivity of Human MATE1 and MATE2-K

Bethzaida Astorga, Sean Ekins, Mark Morales and Stephen H. Wright
Journal of Pharmacology and Experimental Therapeutics June 1, 2012, 341 (3) 743-755; DOI: https://doi.org/10.1124/jpet.112.191577

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Selectivity of Human MATE1 and MATE2-K

Bethzaida Astorga, Sean Ekins, Mark Morales and Stephen H. Wright
Journal of Pharmacology and Experimental Therapeutics June 1, 2012, 341 (3) 743-755; DOI: https://doi.org/10.1124/jpet.112.191577
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