In silico analysis of a few dietary phytochemicals as potential tumor chemo-sensitizers

  • Reza Mamizadeh
  • Zahra Hosseinzadeh
  • Nima Razzaghi-Asl
  • Ali Ramazani
Original Research

Abstract

P-glycoprotein (P-gp) is a membrane ATP-binding cassette (ABC) transporter that extrudes different xenobiotics out of cells. Besides its tissue protection role, overexpression of P-gp on the surface of many neoplastic cells restricts the cell entry of many anti-cancer drugs, the phenomenon which is known as multidrug resistance (MDR). It has been demonstrated that MDR cells can be sensitized toward anti-cancer agents when treated with P-gp inhibitors/modulators known as chemo-sensitizers. Due to the clinical significance and also considering the fact that many P-gp inhibitors are transported by P-gp, the search for more potent and low toxic non-transported chemo-sensitizers is an active area of research. Regarding this, several naturally occurring compounds were reported as MDR reversal agents, a category which is generally referred to as “fourth-generation P-gp inhibitors.” Dietary supplements containing natural products are widely used, and it is possible that they interact with co-administered pharmaceutical substances that are P-gp substrates, leading to altered pharmacokinetic profile. In silico approaches for quantitative and quantitative prediction of binding mechanism of dietary natural products to P-gp may be regarded as appropriate strategy in the early phase of drug discovery projects since they describe structural features of various phytochemicals for interaction with P-gp and pave the way toward alternative and novel anti-MDR scaffolds. In the present contribution, some phytochemicals of turmeric, black pepper, and green tea as commonly consumed dietary sources were subjected to systematic combined in silico analysis including molecular docking and amino acid decomposition analysis through B3LYP functional in association with 6-31G basis set. On the basis of major identified drug binding sites within P-gp internal pocket, modeled natural compounds were categorized as substrate, inhibitor, or modulator while structure binding relationship of each category was developed and elucidated.

Keywords

Cancer P-gp MDR Phytochemicals Quantum mechanical 

Notes

Acknowledgements

The authors are thankful to Ardabil University of Medical Sciences for the support in this project.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta Biomembr 455(1):152–162CrossRefGoogle Scholar
  2. 2.
    Robert J, Jarry C (2003) Multidrug resistance reversal agents. J Med Chem 46(23):4805–4817CrossRefGoogle Scholar
  3. 3.
    Ma JD, Tsunoda SM, Bertino Jr JS, Trivedi M, Beale KK, Nafziger AN (2010) Evaluation of in vivo P-glycoprotein phenotyping probes: a need for validation. Clin Pharmacokinet 49(4):223–237CrossRefGoogle Scholar
  4. 4.
    Rosenberg MF, Callaghan R, Ford RC, Higgins CF (1997) Structure of the multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis. J Biol Chem 272(16):10685–10694CrossRefGoogle Scholar
  5. 5.
    Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22(47):7468–7485CrossRefGoogle Scholar
  6. 6.
    Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323(5922):1718–1722CrossRefGoogle Scholar
  7. 7.
    Schinkel AH, Jonker JW (2012) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv Drug Deliv Rev 55(1):3–29CrossRefGoogle Scholar
  8. 8.
    Sarkadi B, Homolya L, Szakacs G, Varadi A (2006) Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system. Physiol Rev 86(4):1179–1236CrossRefGoogle Scholar
  9. 9.
    Fromm M (2000) P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 38(2):69–74CrossRefGoogle Scholar
  10. 10.
    Gottesman MM, Ling V (2006) The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett 580(4):998–1009CrossRefGoogle Scholar
  11. 11.
    Bayet C, Fazio C, Darbour N, Berger O, Raad I, Chaboud A, Dumontet C, Guilet D (2007) Modulation of P-glycoprotein activity by acridones and coumarins from Citrus sinensis. Phytother Res 21:386–390CrossRefGoogle Scholar
  12. 12.
    DiMarco MP, Edwards DJ, Wainer IW, Ducharme MP (2002) The effect of grapefruit juice and Seville orange juice on the pharmacokinetics of dextromethorphan: the role of gut CYP3A and P-glycoprotein. Life Sci 71:1149–1160CrossRefGoogle Scholar
  13. 13.
    Razzaghi-Asl N, Sepehri S, Ebadi A, Miri R, Shahabipour S (2015) Molecular docking and quantum mechanical studies on biflavonoid structures as BACE-1 inhibitors. Struct Chem 26:607–621CrossRefGoogle Scholar
  14. 14.
    Lomovskaya O, Bostian KA (2006) Practical applications and feasibility of efflux pump inhibitors in the clinic—a vision for applied use. Biochem Pharmacol 71(7):910–918CrossRefGoogle Scholar
  15. 15.
    Chearwaea W, Anuchapreeda S, Nandigama K, Ambudkar SV, Limtrakul P (2004) Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from turmeric powder. Biochem Pharmacol 68:2043–2052CrossRefGoogle Scholar
  16. 16.
    Han Y, Tan TMC, Lim LY (2008) In vitro and in vivo evaluation of the effects of piperine on P-gp function and expression. Toxicol Appl Pharmacol 230:283–289CrossRefGoogle Scholar
  17. 17.
    Kitagawa S, Nabekura T, Kamiyama S (2004) Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells. JPP 56:1001–1005CrossRefGoogle Scholar
  18. 18.
    Nicklisch SC, Rees SD, McGrath AP, Gokirmak T, Bonito LT, Vermeer LM, Cregger C, Loewen G, Sandin S, Chang G, Hamdoun A (2016) Global marine pollutants inhibit P-glycoprotein: environmental levels, inhibitory effects, and cocrystal structure. Sci Adv 2:e1600001CrossRefGoogle Scholar
  19. 19.
    Morris GM, Huey R, Olson AJ (2008) Using AutoDock for ligand-receptor docking. Curr Protoc Bioinformatics 11:34–37Google Scholar
  20. 20.
    Razzaghi-Asl N, Ebadi A, Edraki N, Mehdipour AR, Shahabipour S, Miri R (2012) Response surface methodology in docking study of small molecule BACE-1 inhibitors. J Mol Model 18:4567–4576CrossRefGoogle Scholar
  21. 21.
    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 30:2785–2791CrossRefGoogle Scholar
  22. 22.
    Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662CrossRefGoogle Scholar
  23. 23.
    Wallace AC, Laskowski RA, Thornton JM (1995) LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng 8:127–134CrossRefGoogle Scholar
  24. 24.
    Fogarasi G, Zhou X, Taylor PW, Pulay P (1992) The calculation of ab initio molecular geometries: efficient optimization by natural internal coordinates and empirical correction by off wet forces. J Am Chem Soc 114:8191–8201CrossRefGoogle Scholar
  25. 25.
    Neese F (2011) ORCA—an ab initio, density functional and semiempirical program package. Version 2.8.0, edn. University of BonnGoogle Scholar
  26. 26.
    Hevener KE, Zhao W, Ball DM, Babaoglu K, Qi J, White SW, Lee RE (2009) Validation of molecular docking programs for virtual screening against dihydropteroate synthase. J Chem Inf Model 49(2):444–460CrossRefGoogle Scholar
  27. 27.
    Ferreira RJ, Ferreira MJU, Santos DJVA (2013) Molecular docking characterizes substrate-binding sites and efflux modulation mechanisms within P-glycoprotein. J Chem Inf Model 53:1747–1760CrossRefGoogle Scholar
  28. 28.
    Shapiro AB, Ling V (1997) Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur J Biochem 250:130–137CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Reza Mamizadeh
    • 1
  • Zahra Hosseinzadeh
    • 2
  • Nima Razzaghi-Asl
    • 1
  • Ali Ramazani
    • 2
  1. 1.Department of Medicinal Chemistry, School of PharmacyArdabil University of Medical SciencesArdabilIran
  2. 2.Department of ChemistryUniversity of ZanjanZanjanIran

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