On the mechanism of substrate/non-substrate recognition by P-glycoprotein.

•Molecular Dynamics simulations and docking of drugs performed for P-gp.•Drugs with ER<1 almost do not bind the main binding cavity (MBC) of P-gp.•Drugs with 1≤ER≤2 bind both MBC and other binding sites almost equally.•Strong substrates with ER>2 preferably bind the MBC.•Binding the MBC might be a prerequisite for pumping the compound off the P-gp.