Journal of Integrative Natural Science (통합자연과학논문집)

The Basic Science Institute Chosun University (조선대학교 기초과학연구원)
권호 표지
DOI QR코드

DOI QR Code

Investigation of Binding Modes of the Verapamil and Curcumin into Human P-glycoprotein (P-gp)

  • Gadhe, Changdev G. (Department of Bio-New Drug Development, College of Medicine, Chosun University) ;
  • Cho, Seung Joo (Department of Bio-New Drug Development, College of Medicine, Chosun University)
  • Received : 2013.11.08
  • Accepted : 2013.12.20
  • Published : 2013.12.30
Download PDF
⟨ Previous Next ⟩

Abstract

Human P-gp is a protein responsible for the multidrug resistance (MDR) and causes failure of cancer chemotherapy. Till date no X-ray crystal structure is reported for this membrane protein, which hampers active research in the field. We performed homology modeling to develop three dimensional (3D) model of P-gp, and docking studies of the verapamil and curcumin have been performed to gain insight into the interaction mechanism between inhibitors and P-gp. It was identified that the inhibitors docked into the upper part of P-gp and interacted through the hydrophobic interactions.

Keywords

References

  1. M. M. Gottesman and S. V. Ambudkar, "Overview: ABC transporters and human disease", J. Bioenerg. Biomembr., Vol. 33, pp. 453-458, 2001. https://doi.org/10.1023/A:1012866803188
  2. C. F. Higgins and K. J. Linton, "The ATP switch model for ABC transporters", Nat. Struct. Mol. Biol., Vol. 11, pp. 918-926, 2004. https://doi.org/10.1038/nsmb836
  3. G. D. Leonard, T. Fojo, and S. E. Bates, "The role of ABC transporters in clinical practice", Oncologist, Vol. 8, pp. 411-424, 2003. https://doi.org/10.1634/theoncologist.8-5-411
  4. S. V. Ambudkar, S. Dey, C. A. Hrycyna, M. Ramachandra, I. Pastan, and M. M. Gottesman, "Biochemical, cellular, and pharmacological aspects of the multidrug transporter", Annu. Rev. Pharmacol. Toxicol., Vol. 39, pp. 361-398, 1999. https://doi.org/10.1146/annurev.pharmtox.39.1.361
  5. N. Eswar, B. John, N. Mirkovic, A. Fiser, V. A. Ilyin, U. Pieper, A. C. Stuart, M. A. Marti-Renom, M. S. Madhusudhan, B. Yerkovich, and A. Sali, "Tools for comparative protein structure modeling and analysis", Nucleic Acids Res., Vol. 31, pp. 3375-3380, 2003. https://doi.org/10.1093/nar/gkg543
  6. W. Chearwae, S. Anuchapreeda, K. Nandigama, S.V. Ambudkar, and P. Limtrakul, "Biochemical mechanism of modulation of human P-glycoprotein (ABCB1) by curcumin I, II, and III purified from Turmeric powder", Biochem. Pharmacol., Vol. 68, pp. 2043-2052, 2004. https://doi.org/10.1016/j.bcp.2004.07.009
  7. S. H. R. SYBYL8.1; Tripos Inc., St. Louis, MO 63144, USA (2008).
  8. T. W. Loo and D. M. Clarke, "Identification of Residues in the Drug-binding Domain of Human P-glycoprotein", J. Biol. Chem., Vol. 274, pp. 35388-35392, 1999. https://doi.org/10.1074/jbc.274.50.35388
  9. T. W. Loo and D. M. Clarke, "Identification of Residues within the Drug-binding Domain of the Human Multidrug Resistance P-glycoprotein by Cysteine-scanning Mutagenesis and Reaction with Dibromobimane", J. Biol. Chem., Vol. 275, pp. 39272-39278, 2000. https://doi.org/10.1074/jbc.M007741200
  10. T. W. Loo and D. M. Clarke, "Defining the Drugbinding Site in the Human Multidrug Resistance Pglycoprotein Using a Methanethiosulfonate Analog of Verapamil, MTS-verapamil", J. Biol. Chem., Vol. 276, pp. 14972-14979, 2001. https://doi.org/10.1074/jbc.M100407200
  11. S. G. Aller, J. Yu, A. Ward, Y. Weng, S. Chittaboina, R. Zhuo, P. M. Harrell, Y. T. Trinh, Q. Zhang, I. L. Urbatsch, and G. Chang, "Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding", Science, Vol. 323, pp.1718-1722, 2009. https://doi.org/10.1126/science.1168750
  12. A. C. Wallace, R. A. Laskowski, and J. M. Thornton, "LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions", Protein Eng., Vol. 8, pp. 127-134, 1995. https://doi.org/10.1093/protein/8.2.127
  13. T. W. Loo and D. M. Clarke, "Location of the Rhodamine-binding Site in the Human Multidrug Resistance P-glycoprotein", J. Biol. Chem., Vol. 277, pp. 44332-44338, 2002. https://doi.org/10.1074/jbc.M208433200