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- W1996969897 abstract "P-glycoprotein (P-gp) is one of the key members of the ATP-binding cassette (ABC) transporters family and the major contributor of multidrug resistance against a broad spectrum of drugs in cancer cells. Powered by ATP, P-gp acts as an efflux pump to export a diverse set of hydrophobic molecules, including drugs, out of the cell. These hydrophobic substrates are assumed to enter the translocation pathway of P-gp either via the intracellular side of the cell or directly from the cytoplasmic leaflet of the membrane. In order to characterize the mechanism, residues facilitating drug entry, and translocation, we have taken an approach combining the strengths of molecular dynamics (MD) and molecular docking. A 100 ns MD simulation of membrane-bound inward facing P-gp with Mg2+ and ATP was performed and subsequently used in ensemble docking. Doxorubicin, one of the drug substrates of P-gp, was docked into the defined active sites of 10,000 different snapshots representing the conformational flexibility of the protein in the membrane. Clustered docked poses identified the binding sites and yielded a picture of the sequence of binding events of the substrate within the translocation pathway. Interestingly, a few of the highly populated clusters were located within the region that interacts with the cytoplasmic leaflet of the membrane supporting the recruitment of the substrate laterally and directly from the membrane. Further MD simulations and energetic calculations of representative substrate poses are then used to characterize their real-time binding behavior and dynamics within the intracellular lumen and at the cytoplasmic leaflet of the membrane. This study, for the first time, explored and utilized the dynamic ensemble of conformations of P-gp in molecular docking and dissected important and complex features of its translocation pathway." @default.
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- W1996969897 date "2014-01-01" @default.
- W1996969897 modified "2023-09-30" @default.
- W1996969897 title "Probing Drug-Binding Pathways in P-Glycoprotein with Ensemble Docking" @default.
- W1996969897 doi "https://doi.org/10.1016/j.bpj.2013.11.4334" @default.
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