Structure–Function Relationships in the Human P-Glycoprotein (ABCB1): Insights from Molecular Dynamics Simulations

Abstract

P-glycoprotein (P-gp) is a transmembrane protein belonging to the ATP binding cassette superfamily of transporters, and it is a xenobiotic efflux pump that limits intracellular drug accumulation by pumping compounds out of cells. P-gp contributes to a reduction in toxicity, and has broad substrate specificity. It is involved in the failure of many cancer and antiviral chemotherapies due to the phenomenon of multidrug resistance (MDR), in which the membrane transporter removes chemotherapeutic drugs from target cells. Understanding the details of the ligand–P-gp interaction is therefore critical for the development of drugs that can overcome the MDR phenomenon, for the early identification of P-gp substrates that will help us to obtain a more effective prediction of toxicity, and for the subsequent outdesign of substrate properties if needed. In this work, a series of molecular dynamics (MD) simulations of human P-gp (hP-gp) in an explicit membrane-and-water environment were performed to investigate the effects of binding different compounds on the conformational dynamics of P-gp. The results revealed significant differences in the behaviour of P-gp in the presence of active and non-active compounds within the binding pocket, as different patterns of movement were identified that could be correlated with conformational changes leading to the activation of the translocation mechanism. The predicted ligand–P-gp interactions are in good agreement with the available experimental data, as well as the estimation of the binding-free energies of the studied complexes, demonstrating the validity of the results derived from the MD simulations.

Interaction of a Homologous Series of Amphiphiles with P-glycoprotein in a Membrane Environment—Contributions of Polar and Non-Polar Interactions

“…Support for a size-dependent behavior may be found in the literature, where stipiamide monomers show a low efficiency at small concentrations and a cooperative behavior in the inhibition of IAAP binding to P–gp, while covalent dimers of stipiamide are more efficient and show a simple dependence with concentration [ 101 ] or a more efficient inhibition of P–gp transport activity by bisbenzylisoquinoline alkaloids [ 102 ]. Further evidence for the binding of several molecules in P–gp’s binding pocket has also been obtained from docking studies (e.g., [ 9 , 29 , 79 , 103 , 104 , 105 , 106 , 107 , 108 ]).…”

Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

“…The P-gp transporter has been shown to efflux a diverse range of molecules with varying chemical structures (cyclic, polar, nonpolar, linear, aromatic, linear-lipophilic) and molecular weights (250-4000 Da) (Table 1). Among the first P-gp competitive inhibitors discovered were cyclosporine-A and verapamil [77,78]. In a recent high-throughput screen of 10,804 compounds, Lee et al discovered 90 substrates, 55 of which were novel.…”

Progress, Challenges, and Prospects of Research on the Effect of Gene Polymorphisms on Adverse Reactions to Opioids

“…These efflux transporters are essential for the prevention and treatment of adverse reactions caused by opioid abuse and overdose. ABCB1-coded P-glycoprotein (P-gp) is an efflux transporter that limits intracellular drug accumulation by pumping compounds out of cells [17]. A study in mice showed that P-gp is one of the main components of the blood-cerebrospinal fluid (CSF) barrier.…”