Investigational New Drugs

, Volume 32, Issue 4, pp 618–625 | Cite as

The ability of molecular docking to unravel the controversy and challenges related to P-glycoprotein—a well-known, yet poorly understood drug transporter

  • Maen Zeino
  • Mohamed E. M. Saeed
  • Onat Kadioglu
  • Thomas EfferthEmail author


P-glycoprotein is the most crucial membrane transporter implicated in tumor resistance. Intensive efforts were paid to elucidate the complex mechanism of transport and to identify modulators of this transporter. However, the borderline between substrates and modulators is very thin and identification of the binding sites within P-glycoprotein is complex. Herein, we provide an intensive review of those issues and use molecular docking to assess its ability: first, to differentiate between three groups (substrates, modulators and non-substrates) and second to identify the binding sites. After thorough statistical analysis, we conclude despite the various challenges that molecular docking should not be underestimated as differences between the distinct groups were significant. However, when it comes to defining the binding site, care must be taken, since consensus throughout literature could not be reached.


ABC transporter Cancer Chemotherapy Multidrug resistance 



There is no conflict of interest. We are grateful to the German Academic Exchange Service (DAAD) and the National Research Institute, Sudan for stipends to M.Z. and M.E.M. S., respectively, as well as to the Johannes University, Mainz for an intramural PhD position to O.K.

Supplementary material

10637_2014_98_MOESM1_ESM.pdf (53 kb)
Supplementary Table 1 (PDF 52 kb)
10637_2014_98_MOESM2_ESM.pdf (48 kb)
Supplementary Table 2 (PDF 47 kb)


  1. 1.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–917CrossRefPubMedGoogle Scholar
  2. 2.
    Katzung BG (2007) Basic and Clinical Pharmacology. 10th edition, p 879.Google Scholar
  3. 3.
    Andreoli TE, Bennet JC, Carpenter CCJ, Plum F (1997) Cecil Essentials of Medicine. 4th edition, p 425.Google Scholar
  4. 4.
    Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1981) Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41:1967–72PubMedGoogle Scholar
  5. 5.
    Amiri-Kordestani L, Basseville A, Kurdziel K, Fojo AT, Bates SE (2012) Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies. Drug Resist Updat 15:50–61PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Fudin J, Fontenelle DV, Fudin HR, Carlyn C, Hinden DA, Ashley CC (2013) Potential P-glycoprotein pharmacokinetic interaction of telaprevir with morphine or methadone. J Pain Palliat Care Pharmacother 27:261–7CrossRefPubMedGoogle Scholar
  7. 7.
    Robey RW, Shukla S, Finley EM, Oldham RK, Barnett D, Ambudkar SV, Fojo T, Bates SE (2008) Inhibition of P-glycoprotein (ABCB1)- and multidrug resistance-associated protein 1 (ABCC1)- mediated transport by the orally administered inhibitor, CBT-1((R)). Biochem Pharmacol 75:1302–12PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Leitner I, Nemeth J, Feurstein T, Abrahim A, Matzneller P, Lagler H, Erker T, Langer O, Zeitlinger M (2011) The third-generation P-glycoprotein inhibitor tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration. J Antimicrob Chemother 66:834–9CrossRefPubMedGoogle Scholar
  9. 9.
    Coley HM (2010) Overcoming multidrug resistance in cancer: clinical studies of p-glycoprotein inhibitors. In Multi-Drug Resistance in Cancer, Humana Press, pp. 341–358.Google Scholar
  10. 10.
    Holland IB, Cole SPC, Kuchler K, Higgens CF (2003) ABC proteins: from bacteria to man. Elsevier Science, London, 251Google Scholar
  11. 11.
    Brüggemann EP, Germann UA, Gottesman MM, Pastan I (1989) Two different regions of P-glycoprotein [corrected] are photoaffinity-labeled by azidopine. J Biol Chem 264:15483–8PubMedGoogle Scholar
  12. 12.
    Safa AR (2004) Identification and characterization of the binding sites of P-glycoprotein for multidrug resistance-related drugs and modulators. Curr Med Chem Anticancer Agents 4:1–17PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Loo TW, Bartlett MC, Clarke DM (2003) Substrate-induced conformational changes in the transmembrane segments of human P-glycoprotein. Direct evidence for the substrate induced fit mechanism for drug binding. J Biol Chem 278:13603–6CrossRefPubMedGoogle Scholar
  14. 14.
    Globisch C, Pajeva IK, Wiese M (2008) Identification of putative binding sites of P-glycoprotein based on its homology model. ChemMedChem 3:280–95CrossRefPubMedGoogle Scholar
  15. 15.
    Maki N, Hafkemeyer P, Dey S (2003) Allosteric modulation of human P-glycoprotein. Inhibition of transport by preventing substrate translocation and dissociation. J Biol Chem 278:18132–9CrossRefPubMedGoogle Scholar
  16. 16.
    Badhan R, Penny J (2006) In silico modelling of the interaction of flavonoids with human P-glycoprotein nucleotide-binding domain. Eur J Med Chem 41:285–95CrossRefPubMedGoogle Scholar
  17. 17.
    Ambudkar SV, Kim IW, Xia D, Sauna ZE (2006) The A-loop, a novel conserved aromatic acid subdomain upstream of the Walker A motif in ABC transporters, is critical for ATP binding. FEBS Lett 580:1049–55CrossRefPubMedGoogle Scholar
  18. 18.
    Mechetner EB, Roninson IB (1992) Efficient inhibition of P-glycoprotein-mediated multidrug resistance with a monoclonal antibody. Proc Natl Acad Sci U S A 89:5824–8PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Georges E, Tsuruo T, Ling V (1993) Topology of P-glycoprotein as determined by epitope mapping of MRK-16 monoclonal antibody. J Biol Chem 268:1792–8PubMedGoogle Scholar
  20. 20.
    Nagy H, Goda K, Arceci R, Cianfriglia M, Mechetner E, Szabó G Jr (2001) P-Glycoprotein conformational changes detected by antibody competition. Eur J Biochem 268:2416–20CrossRefPubMedGoogle Scholar
  21. 21.
    Regev R, Assaraf YG, Eytan GD (1999) Membrane fluidization by ether, other anesthetics, and certain agents abolishes P-glycoprotein ATPase activity and modulates efflux from multidrug resistant cells. Eur J Biochem 259:18–24CrossRefPubMedGoogle Scholar
  22. 22.
    Cai C, Zhu H, Chen J (2004) Overexpression of caveolin-1 increases plasma membrane fluidity and reduces P-glycoprotein function in Hs578T/Dox. Biochem Biophys Res Commun 320:868–74CrossRefPubMedGoogle Scholar
  23. 23.
    Wang YH, Li Y, Yang SL, Yang L (2005) Classification of substrates and inhibitors of P-glycoprotein using unsupervised machine learning approach. J Chem Inf Model 45:750–7CrossRefPubMedGoogle Scholar
  24. 24.
    Kim RB (2002) Drugs as P-glycoprotein substrates, inhibitors, and inducers. Drug Metab Rev 34:47–54CrossRefPubMedGoogle Scholar
  25. 25.
    Choi CH (2005) ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal. Cancer Cell Int 5:30PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Bolton E, Wang Y, Thiessen PA, Bryant SH (2008) PubChem: integrated platform of small molecules and biological activities. Chapter 12 IN annual reports in computational chemistry, volume 4. American Chemical Society, WashingtonGoogle Scholar
  27. 27.
    Sadowski J, Gasteiger J, Klebe G (1994) Comparison of automatic three-dimensional model builders using 639 X-Ray structures. J Chem Inf Comput Sci 34:1000–8CrossRefGoogle Scholar
  28. 28.
    Tajima Y, Nakagawa H, Tamura A, Kadioglu O, Satake K, Mitani Y, Murase H, Regasini LO, da Silva Bolzani V, Ishikawa T, Fricker G, Efferth T (2013) Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1. Phytomedicine [Epub ahead of print]Google Scholar
  29. 29.
    Zeino M, Zhao Q, Eichhorn T, Hermann J, Müller R, Efferth T (2013) Molecular docking studies of myxobacterial disorazoles and tubulysins to tubulin. J Biosci Med 3:31–43Google Scholar
  30. 30.
    Hartmann J (2000) Choosing the correct statistical test. University of Alabama, USA,, last retrieved: 12.12.2013.Google Scholar
  31. 31.
    Wise JG (2012) Catalytic transitions in the human MDR1 P-glycoprotein drug binding sites. Biochemistry 51:5125–41PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Klepsch F, Chiba P, Ecker GF (2011) Exhaustive sampling of docking poses reveals binding hypotheses for propafenone type inhibitors of P-glycoprotein. PLoS Comput Biol 7:e1002036PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Tang F, Ouyang H, Yang JZ, Borchardt RT (2004) Bidirectional transport of rhodamine 123 and Hoechst 33342, fluorescence probes of the binding sites on P-glycoprotein, across MDCKMDR1 cell monolayers. J Pharm Sci 93:1185–94CrossRefPubMedGoogle Scholar
  34. 34.
    Loo TW, Clarke DM (2002) Location of the rhodamine-binding site in the human multidrug resistance P-glycoprotein. J Biol Chem 277:44332–8CrossRefPubMedGoogle Scholar
  35. 35.
    Ferreira RJ, Ferreira MJ, dos Santos DJ (2013) Molecular docking characterizes substrate binding sites and efflux modulation mechanisms within P-glycoprotein. J Chem Inf Model 53:1747–60CrossRefPubMedGoogle Scholar
  36. 36.
    Shapiro AB, Ling V (1997) Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur J Biochem 250:130–7CrossRefPubMedGoogle Scholar
  37. 37.
    Loo TW, Clarke DM (2001) Defining the drug-binding site in the human multidrug resistance P-glycoprotein using a methanethiosulfonate analog of verapamil, MTS-verapamil. J Biol Chem 276:14972–9CrossRefPubMedGoogle Scholar
  38. 38.
    Kothandan G, Gadhe CG, Madhavan T, Choi CH, Cho SJ (2011) Docking and 3D-QSAR (quantitative structure activity relationship) studies of flavones, the potent inhibitors of p-glycoprotein targeting the nucleotide binding domain. Eur J Med Chem 46:4078–88CrossRefPubMedGoogle Scholar
  39. 39.
    Bansal T, Jaggi M, Khar RK, Talegaonkar S (2009) Emerging significance of flavonoids as P-glycoprotein inhibitors in cancer chemotherapy. J Pharm Pharm Sci 12:46–78PubMedGoogle Scholar
  40. 40.
    Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem 30:2785–91PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Maen Zeino
    • 1
  • Mohamed E. M. Saeed
    • 1
  • Onat Kadioglu
    • 1
  • Thomas Efferth
    • 1
    Email author
  1. 1.Department of Pharmaceutical Biology, Institute of Pharmacy and BiochemistryJohannes Gutenberg UniversityMainzGermany

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