The ability of molecular docking to unravel the controversy and challenges related to P-glycoprotein—a well-known, yet poorly understood drug transporter

Summary P-glycoprotein is the most crucial membrane transporter implicated in tumor resistance. Intensive efforts were paid to elucidate the complex mechanism of transport and to identify modulators of this transporter. However, the borderline between substrates and modulators is very thin and identification of the binding sites within P-glycoprotein is complex. Herein, we provide an intensive review of those issues and use molecular docking to assess its ability: first, to differentiate between three groups (substrates, modulators and non-substrates) and second to identify the binding sites. After thorough statistical analysis, we conclude despite the various challenges that molecular docking should not be underestimated as differences between the distinct groups were significant. However, when it comes to defining the binding site, care must be taken, since consensus throughout literature could not be reached.