Discovery of the inhibitory effect of a phosphatidylinositol derivative on P-glycoprotein by virtual screening followed by in vitro cellular studies

PLoS One. 2013 Apr 9;8(4):e60679. doi: 10.1371/journal.pone.0060679. Print 2013.


P-glycoprotein is capable of effluxing a broad range of cytosolic and membrane penetrating xenobiotic substrates, thus leading to multi-drug resistance and posing a threat for the therapeutic treatment of several diseases, including cancer and central nervous disorders. Herein, a virtual screening campaign followed by experimental validation in Caco-2, MDKCII, and MDKCII mdr1 transfected cell lines has been conducted for the identification of novel phospholipids with P-gp transportation inhibitory activity. Phosphatidylinositol-(1,2-dioctanoyl)-sodium salt (8∶0 PI) was found to significantly inhibit transmembrane P-gp transportation in vitro in a reproducible-, cell line-, and substrate-independent manner. Further tests are needed to determine whether this and other phosphatidylinositols could be co-administered with oral drugs to successfully increase their bioavailability. Moreover, as phosphatidylinositols and phosphoinositides are present in the human diet and are known to play an important role in signal transduction and cell motility, our finding could be of substantial interest for nutrition science as well.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B / chemistry
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Biological Transport
  • Caco-2 Cells
  • Cell Line
  • Chemistry, Pharmaceutical
  • Cryoelectron Microscopy
  • Digoxin / metabolism
  • Drug Discovery
  • Drug Resistance, Multiple
  • Fluoresceins / metabolism
  • Humans
  • Molecular Docking Simulation
  • Permeability
  • Phosphatidylinositols / chemistry
  • Phosphatidylinositols / metabolism
  • Phosphatidylinositols / pharmacology*
  • Phospholipids / chemistry
  • Phospholipids / metabolism
  • Protein Binding
  • Protein Conformation


  • ATP Binding Cassette Transporter, Subfamily B
  • Fluoresceins
  • Phosphatidylinositols
  • Phospholipids
  • Digoxin
  • fluorexon

Grant support

This work has received funding from the Excellence Initiative of the German Federal and State Governments through the Junior Research GroupProgramme (ZUK 43), by the Federal State of Baden-Württemberg (Ministry of Science, Research, and Arts), and by Phospholipid e.V. (Heidelberg, Germany). The article processing charge was funded by the German Research Foundation (DFG) and the Albert Ludwigs University Freiburg in the funding programme Open Access Publishing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.