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Journal of Molecular Modeling

, Volume 19, Issue 1, pp 227–238 | Cite as

A plausible explanation for enhanced bioavailability of P-gp substrates in presence of piperine: simulation for next generation of P-gp inhibitors

  • Durg Vijay Singh
  • Madan M. Godbole
  • Krishna MisraEmail author
Original Paper

Abstract

P-glycoprotein (P-gp) has a major role to play in drug pharmacokinetics and pharmacodynamics, since it effluxes many cytotoxic hydrophobic anticancer drugs from gastrointestinal tract, brain, liver and kidney. Piperine is known to enhance the bioavailability of curcumin, as a substrate of P-gp by at least 2000 %. Besides these at least 50 other substrates and inhibitors of P-gp have been reported so far. All P-gp inhibitors have diverse structures. Although little is known about binding of some flavonoids and steroids at the NBD (nucleotide binding domain) of P-gp in the vicinity of ATP binding site inhibiting its hydrolysis, a valid explanation of how P-gp accommodates such a diverse set of inhibitors is still awaited. In the present study, piperine up to 100 μM has not shown observable cytotoxic effect on MDCK cell line, and it has been shown to accumulate rhodamine by fluorescence microscopy and fluorescent activated cell sorter in MDCK cells. Computational simulation for piperine and some first and second generation P-gp inhibitors has shown that these dock at the NBD site of P-gp. A comparative simulation study has been carried out regarding their docking and binding energies. Binding conformation of P-gp co-crystallized complexes with ADP, AMP-PNP (Adenylyl-imidodiphosphate), and ATP were compared with piperine. The receptor based E-pharmacophore of docked piperine has been simulated to find common features amongst P-gp inhibitors. Finally it has been concluded that piperine could be utilized as base molecule for design and development of safe non-toxic inhibitor of P-gp in order to enhance the bioavailability of most of its substrates.

Figure

Piperine binds between the consensus sequence of Walker A/P loop and Walker C loop (linker peptide) at the nucleotide binding domain which is crucial for ATP coupled efflux through P-gp. ATP binding competes with piperine. This explains why piperine enhances the bioavailability of its substrate like curcumin by 2000 %

Keywords

Docking E-pharmacophores Homology modeling Immunofluorscence P-glycoprotein (P-gp) P-gp inhibitors Piperine 

Supplementary material

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Fig. 5S (DOC 59 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Durg Vijay Singh
    • 1
  • Madan M. Godbole
    • 2
  • Krishna Misra
    • 3
    Email author
  1. 1.Department of BioinformaticsIndian Institute of Information TechnologyAllahabadIndia
  2. 2.Department of Endocrinology SGPGI-MS CampusLucknowIndia
  3. 3.Center of Biomedical Magnetic ResonanceLucknowIndia

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