Interactions of the multidrug resistance modulators tariquidar and elacridar and their analogues with P-glycoprotein.
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.
Institute of Biophysics & Biomedical Engineering (IBPhBME), Bulgarian Academy of Sciences, Acad. G. Bonchev Str. Bl. 105, 1113 Sofia (Bulgaria). pajeva@biomed.bas.bg.
Ilza K
IK
Pajeva
Katja
K
Sterz
Matthias
M
Christlieb
Kerstin
K
Steggemann
Federico
F
Marighetti
Michael
M
Wiese
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000166:Acridines / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism; D020112:Rhodamine 123 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D001562:Benzimidazoles; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D020112:Rhodamine 123; C402343:tariquidar; C083501:Elacridar; C017807:bisbenzimide ethoxide trihydrochloride
P‐glycoprotein; binding sites; elacridar; interactions; tariquidar