title: Do adsorbed drugs onto P-glycoprotein influence its efflux capability?
abstract: The membrane biophysical aspects by which multidrug resistance (MDR) relate to the ABC transporter function still remain largely unknown. Notwithstanding the central role that efflux pumps like P-glycoprotein have in MDR onset, experimental studies classified additionally the lipid micro-environment where P-gp is inserted as a determinant for the increased efflux capability demonstrated in MDR cell lines. Recently, a nonlinear model for drug-membrane interactions showed that, upon drug adsorption, long-range mechanical alterations are predicted to affect the P-gp ATPase function at external drug concentrations of ∼10-100 μM. However, our results also show that drug adsorption may also occur at P-gp nucleotide-binding domains where conformational changes drive the efflux cycle. Thus, we assessed the effect of drug adsorption to both protein-water and lipid-water interfaces by means of molecular dynamics simulations. The results show that free energies of adsorption are lower for modulators in both lipid/water and protein/water interfaces. Important differences in drug-protein interactions, protein dynamics and membrane biophysical characteristics were observed between the different classes. Therefore, we hypothesize that drug adsorption to the protein and lipid-water interface accounts for a complex network of events that affect the ability of transporters to efflux drugs.
authors.affiliation: Research Institute for Medicines (iMed.Ulisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, Lisboa, Portugal. rjdgferreira@ff.ulisboa.pt mjuferreira@ff.ulisboa.pt.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Ferreira
authors.forename: Maria-José U
authors.initials: MJ
authors.lastname: Ferreira
authors.forename: Daniel J V A
authors.initials: DJ
authors.lastname: dos Santos
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000327:Adsorption; D001665:Binding Sites; D001692:Biological Transport; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D055595:Mechanical Phenomena; D056004:Molecular Dynamics Simulation; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008051:Lipid Bilayers; D004364:Pharmaceutical Preparations; D014867:Water; D000255:Adenosine Triphosphate