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Abstract:

The human multidrug resistance (MDR) P-glycoprotein (P-gp) mediates the extrusion of chemotherapeutic drugs from cancer cells. Modulators are relevant pharmaceutical targets since they are intended to control or to inhibit its pumping activity. In the present work, a common binding site for Rhodamine 123 and modulators with different modulation activity was found by molecular docking over the crystal structure of the mouse P-gp. The modulators involved a family of compounds, including derivatives of propafenone (3-phenylpropiophenone nucleus) and XR9576 (tariquidar). Our results showed that the relative binding energies estimated by molecular docking were in good correlation with the experimental activities. Preliminary classical molecular dynamics results on selected P-gp/modulator complexes were also performed in order to understand the nature of the prevalent molecular interactions and the possible main molecular features that characterize a modulator. Besides, the results obtained with a human P-gp homology model from the mouse structure are also presented and analyzed. Our observations suggest that the hydrophobicity and molecular flexibility are the main features related to the inhibitory activity. The latter factor would increase the modulator ability to fit the aromatic rings inside the transmembrane domain. © 2013 Elsevier Inc.

Registro:

Documento: Artículo
Título:Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study
Autor:Jara, G.E.; Vera, D.M.A.; Pierini, A.B.
Filiación:Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar Del Plata, Funes 3550, 7600 Mar del Plata, Argentina
INQUIMAE-CONICET, Departamento de Química Inorgánica, Ciudad Universitaria, Buenos Aires, Argentina
Palabras clave:ABC transporters; Free energies of binding; MDR; Molecular docking; Molecular dynamics; P-glycoprotein; ABC transporter; Classical molecular dynamics; Experimental activities; Human multidrug resistance; MDR; Molecular docking; P-glycoprotein; Relative binding energies; Activation analysis; Glycoproteins; Mammals; Molecular dynamics; Molecular modeling; Modulators; multidrug resistance protein; propafenone; rhodamine 123; tariquidar; article; crystal structure; drug binding site; drug inhibition; human; hydrophobicity; molecular docking; molecular dynamics; molecular interaction; mouse; nonhuman; priority journal; protein localization; ABC transporters; Free energies of binding; MDR; Molecular docking; Molecular dynamics; P-glycoprotein; Amino Acid Motifs; Animals; Binding Sites; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Hydrophobic and Hydrophilic Interactions; Mice; Molecular Docking Simulation; Molecular Dynamics Simulation; P-Glycoproteins; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Quinolines; Rhodamine 123; Thermodynamics
Año:2013
Volumen:46
Página de inicio:10
Página de fin:21
DOI: http://dx.doi.org/10.1016/j.jmgm.2013.09.001
Título revista:Journal of Molecular Graphics and Modelling
Título revista abreviado:J. Mol. Graph. Model.
ISSN:10933263
CODEN:JMGMF
CAS:multidrug resistance protein, 149200-37-3, 208997-77-7; propafenone, 34183-22-7, 54063-53-5; rhodamine 123, 62669-70-9; tariquidar, 206873-63-4
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_10933263_v46_n_p10_Jara

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Citas:

---------- APA ----------
Jara, G.E., Vera, D.M.A. & Pierini, A.B. (2013) . Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study. Journal of Molecular Graphics and Modelling, 46, 10-21.
http://dx.doi.org/10.1016/j.jmgm.2013.09.001
---------- CHICAGO ----------
Jara, G.E., Vera, D.M.A., Pierini, A.B. "Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study" . Journal of Molecular Graphics and Modelling 46 (2013) : 10-21.
http://dx.doi.org/10.1016/j.jmgm.2013.09.001
---------- MLA ----------
Jara, G.E., Vera, D.M.A., Pierini, A.B. "Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study" . Journal of Molecular Graphics and Modelling, vol. 46, 2013, pp. 10-21.
http://dx.doi.org/10.1016/j.jmgm.2013.09.001
---------- VANCOUVER ----------
Jara, G.E., Vera, D.M.A., Pierini, A.B. Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study. J. Mol. Graph. Model. 2013;46:10-21.
http://dx.doi.org/10.1016/j.jmgm.2013.09.001