Skip to main content
SpringerLink
Log in

Molecular dynamics simulations of inclusion complexation of glycyrrhizic acid and cyclodextrins (1:1) in water

  • Original Article
  • Published:
Journal of Inclusion Phenomena and Macrocyclic Chemistry Aims and scope Submit manuscript

Abstract

By means of molecular dynamics (MD) simulations, we analyzed the formation of inclusion complex consisting of cyclodextrins and the triterpene glycoside, glycyrrhizic acid, to obtain information about the transient binding pathway and the stable complex structures in equilibrium. For each of the two possible orientations of a glycyrrhizic acid molecule, β- and γ-cyclodextrins were initially positioned on 20 different sites of the molecule at intervals of 1 Å, and the MD run was performed for 0.8 nsec for the sampling conformations. The position-dependent energy contributions derived from van der Waals interactions and electrostatic interactions showed that there exist two distribution gaps responsible for the formation of β-cyclodextrin complexes, indicating that glycyrrhizic acid could not pass through the hydrophobic pocket of β-cyclodextrin, as opposed to γ-cyclodextrin. In the most stable complex structures for both β- and γ-cyclodextrins, the glucuronic acid of glycyrrhizic acid binds to the hydrophobic pocket of cyclodextrins. This is also consistent with the analysis of hydrogen bonding. These energy contributions are larger for the binding to γ-cyclodextrin than to β-cyclodextrin, which correlates well with the results of isothermal titration calorimetry experiments. We also analyzed configurational entropies based on the trajectory of the MD runs, which showed that there would be little difference in configurational entropy on the binding entropy change between β- and γ- cyclodextrins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Szejtli, J.: Introduction and general overview of cyclodextrin chemistry. Chem. Rev. 98, 1743–1753 (1998)

    Article  CAS  Google Scholar 

  2. Rekharsky, M.V., Inoue, Y.: Complexation thermodynamics of cyclodextrins. Chem. Rev. 98, 1875–1918 (1998)

    Article  CAS  Google Scholar 

  3. Biernacka, J., Betlejewska-Kielak, K., Witowska-Jarosz, J., Kłosińska-Szmurło, E., Mazurek, A.P.: Mass spectrometry and molecular modeling studies on the inclusion complexes between alendronate and β-cyclodextrin. J. Incl. Phenom. Macrocycl. Chem. 78, 437–443 (2014)

    Article  CAS  Google Scholar 

  4. Bonnet, V., Gervaise, C., Djedaïni-Pilard, F., Furlan, A., Sarazin, C.: Cyclodextrin nanoassemblies: a promising tool for drug delivery. Drug Discov. Today 20, 1120–1126 (2015)

    Article  CAS  Google Scholar 

  5. Polyakov, N.E., Kispert, L.D.: Water soluble biocompatible vesicles based on polysaccharides and oligosaccharides inclusion complexes for carotenoid delivery. Carbohydr. Polym. 128, 207–219 (2015)

    Article  CAS  Google Scholar 

  6. Castronuovo, G., Niccoli, M.: Thermodynamics of inclusion complexes of natural and modified cyclodextrins with propranolol in aqueous solution at 298 K. Bioorg. Med. Chem. 14, 3883–3887 (2006)

    Article  CAS  Google Scholar 

  7. Izutani, Y., Kanaori, K., Imoto, T., Oda, M.: Interaction of gymnemic acid with cyclodextrins analyzed by isothermal titration calorimetry, NMR and dynamic light scattering. FEBS J. 272, 6154–6160 (2005)

    Article  CAS  Google Scholar 

  8. Mizutani, K., Kuramoto, T., Tamura, Y., Ohtake, N., Doi, S., Nakaura, M., Tanaka, O.: Sweetness of glycyrrhetic acid 3-O-β-d-monoglucuronide and the related glycosides. Biosci. Biotechnol. Biochem. 58, 554–555 (1994)

    Article  CAS  Google Scholar 

  9. Ming, L.J., Yin, A.C.Y.: Therapeutic effects of glycyrrhizic acid. Nat. Prod. Commun. 8, 415–418 (2013)

    CAS  Google Scholar 

  10. Haghshenas, V., Fakhari, S., Mirzaie, S., Rahmani, M., Farhadifar, F., Pirzadeh, S., Jalili, A.: Glycyrrhetinic acid inhibits cell growth and induces apoptosis in ovarian cancer A2780 cells. Adv. Pharm. Bull. 4, 437–441 (2014)

    CAS  Google Scholar 

  11. Zhao, M.X., Ji, L.N., Mao, Z.W.: β-Cyclodextrin/glycyrrhizic acid functionalised quantum dots selectively enter hepatic cells and induce apoptosis. Chemistry 18, 1650–1658 (2012)

    Article  CAS  Google Scholar 

  12. Izutani, Y., Kanaori, K., Oda, M.: Aggregation property of glycyrrhizic acid and its interaction with cyclodextrins analyzed by dynamic light scattering, isothermal titration calorimetry, and NMR. Carbohydr. Res. 392, 25–30 (2014)

    Article  CAS  Google Scholar 

  13. Wang, J., Wolf, R.M., Caldwell, J.W., Kollman, P.A., Case, D.A.: Development and testing of a general amber force field. J. Comput. Chem. 25, 1157–1174 (2004)

    Article  CAS  Google Scholar 

  14. Jakalian, A., Bush, B.L., Jack, D.B., Bayly, C.I.: Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method. J. Comput. Chem. 21, 132–146 (2000)

    Article  CAS  Google Scholar 

  15. Jakalian, A., Jack, D.B., Bayly, C.I.: Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation. J. Comput. Chem. 23, 1623–1641 (2002)

    Article  CAS  Google Scholar 

  16. Morikami, K., Nakai, T., Kidera, A., Saito, M., Nakamura, H.: Presto (protein engineering simulator): a vectorized molecular mechanics program for biopolymers. Comput. Chem. 16, 243–248 (1992)

    Article  CAS  Google Scholar 

  17. Schlitter, J.: Estimation of absolute and relative entropies of macromolecules using the covariance matrix. Chem. Phys. Lett. 215, 617–621 (1993)

    Article  CAS  Google Scholar 

  18. Oda, M., Furukawa, K., Ogata, K., Sarai, A., Nakamura, H.: Thermodynamics of specific and non-specific DNA binding by the c-Myb DNA-binding domain. J. Mol. Biol. 276, 571–590 (1998)

    Article  CAS  Google Scholar 

  19. Yu, Y., Chipot, C., Cai, W., Shao, X.: Molecular dynamics study of the inclusion of cholesterol into cyclodextrins. J. Phys. Chem. B 110, 6372–6378 (2006)

    Article  CAS  Google Scholar 

  20. Semino, R., Rodríguez, J.: Molecular dynamics study of ionic liquids complexation within β-cyclodextrins. J. Phys. Chem. B 119, 4865–4872 (2015)

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Mr. Nobutaka Komichi for technical support.

Author information

Authors and Affiliations

  1. Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, 1-5 Hangi-cho, Shimogamo, Sakyo-ku, Kyoto, Kyoto, 606-8522, Japan

    Masayuki Oda & Masataka Kuroda

  2. Discovery Technology Laboratories, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa, 227-0033, Japan

    Masataka Kuroda

Authors
  1. Masayuki Oda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masataka Kuroda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masayuki Oda.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oda, M., Kuroda, M. Molecular dynamics simulations of inclusion complexation of glycyrrhizic acid and cyclodextrins (1:1) in water. J Incl Phenom Macrocycl Chem 85, 271–279 (2016). https://doi.org/10.1007/s10847-016-0626-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10847-016-0626-z

Keywords

Search

Navigation