P-glycoprotein and Multidrug-Resistant Cancer
In silico identified targeted inhibitors of P-glycoprotein overcome multidrug resistance in human cancer cells in culture.
Pharmacol Res Perspect. 2015 Oct;3(5):e00170. doi: 10.1002/prp2.170. Epub 2015 Aug 10.
Biochemistry. 2015 Jul 21;54(28):4374-90. doi: 10.1021/acs.biochem.5b00018. Epub 2015 Jul 10.
Abstract Excerpt: “P-Glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell…We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11-12 Å through the plane of the membrane… Methylpyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane…A mechanism of inhibition by tariquidar that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp is presented.