Binding of Modulators to the Mouse and Human Multidrug Resistance (MDR) P-glycoprotein. A Computational Study

GABRIEL E. JARA; D. MARIANO A. VERA*; ADRIANA B. PIERINI

JOURNAL OF MOLECULAR GRAPHICS & MODELLING.

ELSEVIER SCIENCE INC

Lugar: San Francisco; Año: 2013 vol. 46 p. 10 - 21

1093-3263

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 family of such modulators, including derivatives of the propafenone (3-phenylpropiophenone nucleus) and XR9576 (tariquidar), were docked into a structural model of the mouse P-gp, locating the main binding regions. 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 interactions. Finally, the results obtained with a human P-gp homology model from the mouse structure are also presented and analyzed. Our observations showed that the hydrophobicity and molecular flexibility, the latter for increasing the ability to fit the aromatic rings inside the transmembrane domain, are the main features related to the inhibitory activity.