Molecular Energetics of Doxorubicin Pumping by Human P‑Glycoprotein

The
pumping of antitumor drugs by P-glycoprotein (P-gp) causes
multidrug resistance (MDR) and consequent failure of chemotherapy.
However, the understanding on the molecular mechanism of P-gp for
transporting substrates is still far from adequate. Herein, the transport
of a typical antitumor drug, doxorubicin, by P-gp is investigated
using targeted molecular dynamics (MD) simulations and molecular mechanics
Poisson–Boltzmann surface area (MM-PBSA) analysis. The MM-PBSA
analysis identifies the driving forces for the transport of doxorubicin
toward the extracellular space as electrostatic repulsions in the
initial stage, which are contributed by positively charged residues
(R148, K181, K189, K285, K291, K734, R789, K826, K934, and K1000)
and then hydrophobic interactions provided by hydrophobic residues
(L65, M69, F336, I340, F343, Y953, V982, F983, and M986). The contributions
of these residues are further validated by targeted MD simulations,
which shows blocked pumping after the mutation of these important
residues to glycine. The MM-PBSA and minimum distance analyses of
each residue during the transport reveal that the positively charged
residues promote the transport of doxorubicin through long-range electrostatic
repulsions and the hydrophobic residues provide a pathway through
continuous hydrophobic interactions to maintain the transport. The
results have thus provided molecular insights into the function of
P-gp and would be beneficial in the design of potent P-gp inhibitors
against MDR in the medication of cancers.