The P-glycoprotein is an efflux transporter that expels substances out of the
cells and has an important impact on the pharmacokinetic and pharmacodynamic properties
of drugs. The study of the interactions between ligands and the P-glycoprotein has
implications in the design of Central Nervous System drugs and their transport across the
blood-brain barrier. Moreover, since the P-glycoprotein is overexpressed in some types of
cancers, the protein is responsible for expelling the drug therapies from the cells, and
hence, for drug resistance. In this review, we describe different P-glycoprotein binding
sites reported for substrates, inhibitors and modulators, and focus on molecular docking
studies that provide useful information about drugs and P-glycoprotein interactions.
Docking in crystallized structures and homology models showed potential in the detection
of the binding site and key residues responsible for ligand recognition. Moreover, virtual
screening through molecular docking discriminates P-glycoprotein ligands from decoys.
We also discuss challenges and limitations of molecular docking simulations applied to
this particular protein. Computational structure-based approaches are very helpful in the
study of novel ligands that interact with the P-glycoprotein and provide insights to understand
the P-glycoprotein molecular mechanism of action.