Molecular docking characterizes substrate-binding sites and efflux modulation mechanisms within P-glycoprotein

J Chem Inf Model. 2013 Jul 22;53(7):1747-60. doi: 10.1021/ci400195v. Epub 2013 Jul 10.


P-Glycoprotein (Pgp) is one of the best characterized ABC transporters, often involved in the multidrug-resistance phenotype overexpressed by several cancer cell lines. Experimental studies contributed to important knowledge concerning substrate polyspecificity, efflux mechanism, and drug-binding sites. This information is, however, scattered through different perspectives, not existing a unifying model for the knowledge available for this transporter. Using a previously refined structure of murine Pgp, three putative drug-binding sites were hereby characterized by means of molecular docking. The modulator site (M-site) is characterized by cross interactions between both Pgp halves herein defined for the first time, having an important role in impairing conformational changes leading to substrate efflux. Two other binding sites, located next to the inner leaflet of the lipid bilayer, were identified as the substrate-binding H and R sites by matching docking and experimental results. A new classification model with the ability to discriminate substrates from modulators is also proposed, integrating a vast number of theoretical and experimental data.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Animals
  • Binding Sites
  • Biological Transport
  • Databases, Protein
  • Humans
  • Mice
  • Molecular Docking Simulation*
  • Pharmaceutical Preparations / metabolism
  • Protein Binding
  • Protein Conformation


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Pharmaceutical Preparations