Molecular Energetics of Doxorubicin Pumping by Human P-Glycoprotein.

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Molecular Energetics of Doxorubicin Pumping by Human P-Glycoprotein.

J Chem Inf Model. 2019 Aug 05;:

Authors: Wang L, Zhang L, Liu F, Sun Y

Abstract
The pumping of anti-tumor 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 anti-tumor 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 towards 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.

PMID: 31381334 [PubMed - as supplied by publisher]