Quantification and characterization of P-glycoprotein-substrate interactions

Biochemistry
Ewa Gatlik-LandwojtowiczAnna Seelig

Abstract

It is generally accepted that P-glycoprotein binds its substrates in the lipid phase of the membrane. Quantification and characterization of the lipid-transporter binding step are, however, still a matter of debate. We therefore selected 15 structurally diverse drugs and measured the binding constants from water to the activating (inhibitory) binding region of P-glycoprotein, K(tw(1)) (K(tw(2))), as well as the lipid-water partition coefficients, K(lw). The former were obtained by measuring the concentrations of half-maximum activation (inhibition), K(1) (K(2)), in living NIH-MDR-G185 mouse embryo fibroblasts using a Cytosensor microphysiometer, and the latter were derived from surface activity measurements. This allowed determination of the membrane concentration of drugs at half-maximum P-glycoprotein activation (C(b(1)) = (0.02 to 67) mmol/L lipid), which is much higher than the corresponding aqueous concentration (K(1) = (0.02 to 376) microM). Moreover we determined the free energy of drug binding from water to the activating binding region of the transporter (DeltaG degrees (tw(1)) = (-30 to -54) kJ/mol), the free energy of drug partitioning into the lipid membrane (DeltaG degrees (lw) = (-23 to -34) kJ/mol), and, as the d...Continue Reading

Citations

Dec 1, 2009·Future Medicinal Chemistry·David D StenehjemGrant W Anderson
Jul 21, 2010·Nature Chemical Biology·David Parcej, Robert Tampé
Jun 7, 2008·Microbiology and Molecular Biology Reviews : MMBR·Amy L DavidsonJue Chen
May 1, 2009·Journal of Medicinal Chemistry·Michael K GannonMichael R Detty
Jun 16, 2012·The Journal of Biological Chemistry·Valentina CorradiD Peter Tieleman
Sep 29, 2007·Journal of Molecular Neuroscience : MN·Anna Seelig
Jan 12, 2007·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Frances J Sharom
Dec 10, 2013·Trends in Biochemical Sciences·Kelvin WongIan D Kerr
Apr 27, 2013·Molecular Pharmaceutics·Catia MarzoliniAnna Seelig
Oct 4, 2006·Expert Opinion on Drug Metabolism & Toxicology·Anna Seelig, Grégori Gerebtzoff
Feb 1, 2012·Bioorganic & Medicinal Chemistry Letters·Zhicai WuDong-Ming Shen
Sep 21, 2013·Journal of Chemical Information and Modeling·Freya KlepschGerhard F Ecker
Jun 21, 2014·Molecular Pharmaceutics·Daria Y Alakhova, Alexander V Kabanov
Oct 17, 2009·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Christel A S BergströmAnja Sandström
Jan 13, 2009·Biochimica Et Biophysica Acta·Markus A Seeger, Hendrik W van Veen
Jan 13, 2009·Advanced Drug Delivery Reviews·E NicolleA Di Pietro
Oct 18, 2008·Bioorganic & Medicinal Chemistry Letters·Brandon J TurunenGunda I Georg
Sep 25, 2007·Bioorganic & Medicinal Chemistry·Henrik MüllerMichael Wiese
Feb 24, 2007·Biochemical and Biophysical Research Communications·John GolinLeopold May
Jun 6, 2009·The FEBS Journal·Tomomi SatoHiroaki Kato
Nov 23, 2012·Insect Molecular Biology·Jason SimmonsCam Donly
Jan 1, 2012·Archives of Insect Biochemistry and Physiology·Ravindra M AuradeKuruba Sreeramulu
Jul 20, 2010·BioFactors·Yogendra P Singh, Ram A Singh
Aug 22, 2006·Biophysical Chemistry·Sofia A C LimaPaula Gameiro
Oct 5, 2011·Essays in Biochemistry·Joseph K ZolnerciksKenneth J Linton
Dec 17, 2009·Biochimica Et Biophysica Acta·Pierluigi NerviAnna Seelig
Apr 27, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Hongming LiuBaojian Wu
Jun 11, 2011·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·H GlavinasP Krajcsi
Apr 10, 2012·Gynecologic Oncology·Paul A WenderNelson N H Teng
May 19, 2012·Bioorganic & Medicinal Chemistry·Vasanthanathan PoongavanamGerhard F Ecker

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.