Molecular Docking Characterizes Substrate-Binding Sites and Efflux Modulation Mechanisms within P‑Glycoprotein.

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.