Interactions of the Multidrug Resistance Modulators Tariquidar and Elacridar and their Analogues with P-glycoprotein

Authors

  • Prof. Dr. Ilza K. Pajeva,

    Corresponding author
    1. Institute of Biophysics & Biomedical Engineering (IBPhBME), Bulgarian Academy of Sciences, Acad. G. Bonchev Str. Bl. 105, 1113 Sofia (Bulgaria)
    • Institute of Biophysics & Biomedical Engineering (IBPhBME), Bulgarian Academy of Sciences, Acad. G. Bonchev Str. Bl. 105, 1113 Sofia (Bulgaria)
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  • Dr. Katja Sterz,

    1. Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Matthias Christlieb,

    1. Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Dr. Kerstin Steggemann,

    1. Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Federico Marighetti,

    1. Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Prof. Dr. Michael Wiese

    Corresponding author
    1. Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
    • Pharmaceutical Chemistry II, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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Abstract

Tariquidar and elacridar are among the most potent inhibitors of the multidrug resistance transporter P-glycoprotein (P-gp), but how they interact with the protein is yet unknown. In this work, we describe a possible way in which these inhibitors interact with P-gp. We rely on structure–activity relationship analysis of a small group of tariquidar and elacridar analogues that was purposefully selected, designed, and tested. Structural modifications of the compounds relate to the presence or absence of functional groups in the tariquidar and elacridar scaffolds. The activity of the compounds was evaluated by their effects on the accumulation of P-gp substrates rhodamine 123 and Hoechst 33342 in resistant tumor cells. The data allow estimation of the ability of the compounds to interact with the experimentally proposed R- and H-sites to which rhodamine 123 and Hoechst 33342 bind, respectively. Using an inward-facing homology model of human P-gp based on the crystallographic structure of mouse P-gp, we demonstrate that these binding sites may overlap with the binding sites of the QZ59 ligands co-crystallized with mouse P-gp. Based on this SAR analysis, and using flexible alignment and docking, we propose possible binding modes for tariquidar and elacridar. Our results suggest the possibility for the studied compounds to bind to sites that coincide or overlap with the binding sites of rhodamine 123 and Hoechst 33342. These results contribute to further understanding of structure–function relationships of P-gp and can help in the design of selective and potent P-gp inhibitors with potential clinical use.

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