title: Structural association of nonsteroidal anti-inflammatory drugs with lipid membranes.
abstract: The location and distribution of ibuprofen, a model nonsteroidal anti-inflammatory drug, in a phospholipid bilayer was examined in molecular detail by a combination of neutron diffraction and computer simulations. In addition to their use as antipyretic, analgesic, and anti-inflammatory drugs, such nonsteroidal anti-inflammatory drugs are used in the treatment of a number of diseases including cancer and Alzheimer's. As a side effect, they have been known to cause gastrointestinal toxicity, although the molecular mechanism of their action is poorly understood. In this study, we have used contrast variation-based neutron diffraction to determine the position of the drug in a 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine lipid bilayer and explore changes to the bilayer structure upon drug incorporation. In its charged state, the drug was found to locate in the polar headgroup region of the phospholipid bilayer, to induce bilayer thinning, and to increase the number of water molecules closely associated with the bilayer. These structural insights are consistent with molecular dynamics simulations and earlier macroscopic experiments of vesicle structure and dynamics. Using MD simulations, the neutral ibuprofen, typically observed at low pH and inaccessible to the diffraction studies, was found to locate deeper within the bilayer than the charged form.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas 77204, United States.
authors.forename: Mohan Babu
authors.initials: MB
authors.lastname: Boggara
authors.forename: Mihaela
authors.initials: M
authors.lastname: Mihailescu
authors.forename: Ramanan
authors.initials: R
authors.lastname: Krishnamoorti
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007052:Ibuprofen / Q000737:chemistry / Q000494:pharmacology; D008051:Lipid Bilayers / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D033363:Neutron Diffraction; D014867:Water / Q000737:chemistry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008051:Lipid Bilayers; D014867:Water; D007052:Ibuprofen