On interactions of P-glycoprotein with various anti-tumor drugs by binding free energy calculations.

P-glycoprotein (P-gp, MDR1), one of ATP-binding cassette transporters, may confer tumor cells cross-resistance to chemotherapeutics. A large amount of P-gp inhibitors were designed to inhibit the multidrug resistance (MDR) feature of P-gp. However, no sufficient researches were reported to explore the correlation between binding capacity and drug property by experiment. Without particular drug property found to inhibit the MDR feature of P-gp, the orientation of drug design is indefinite. In this work, 10 representative cancer drugs with various properties are used to bind with P-gp by molecular dynamics simulation. Binding free energy between P-gp and 10 drugs ranges -139 to -253 kJ/mol. It reveals that the promiscuity nature of P-gp is in light of the similar binding free energy in separate P-gp-ligand binding systems. The binding effect of P-gp and drugs correlates well with the size of drugs and has no apparent correlation with the polarity of each drug. The key reason is that van der Waal's interaction occupies most of the total binding free energy, and it is led by the number of atoms in the drugs. Two transmembrane segments (TM6 and TM12) and three types of amino acids (PHE, MET, and GLN) are vital in binding drugs with van der Waal's energy, which evident the influence between binding stability and size of drugs. This work provides the cause and theoretical basis for the promiscuity nature of P-gp.Communicated by Ramaswamy H. Sarma.