title: In silico pharmacology: Drug membrane partitioning and crossing.
abstract: Over the past decade, molecular dynamics (MD) simulations have become particularly powerful to rationalize drug insertion and partitioning in lipid bilayers. MD simulations efficiently support experimental evidences, with a comprehensive understanding of molecular interactions driving insertion and crossing. Prediction of drug partitioning is discussed with respect to drug families (anesthetics; β-blockers; non-steroidal anti-inflammatory drugs; antioxidants; antiviral drugs; antimicrobial peptides). To accurately evaluate passive permeation coefficients turned out to be a complex theoretical challenge; however the recent methodological developments based on biased MD simulations are particularly promising. Particular attention is paid to membrane composition (e.g., presence of cholesterol), which influences drug partitioning and permeation. Recent studies concerning in silico models of membrane proteins involved in drug transport (influx and efflux) are also reported here. These studies have allowed gaining insight in drug efflux by, e.g., ABC transporters at an atomic resolution, explicitly accounting for the mandatory forces induced by the surrounded lipid bilayer. Large-scale conformational changes were thoroughly analyzed.
authors.affiliation: INSERM UMR 850, Univ. Limoges, Faculty of Pharmacy, 2 rue du Dr Marcland, F-87025, Limoges, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Di Meo
authors.affiliation: LCSN, Univ. Limoges, Faculty of Pharmacy, 2 rue du Dr Marcland, F-87025, Limoges, France.
authors.forename: Gabin
authors.initials: G
authors.lastname: Fabre
authors.affiliation: Regional Centre for Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky̿ University, Olomouc, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Berka
authors.affiliation: INSERM UMR 850, Univ. Limoges, Faculty of Pharmacy, 2 rue du Dr Marcland, F-87025, Limoges, France.
authors.forename: Tahani
authors.initials: T
authors.lastname: Ossman
authors.affiliation: INSERM UMR 850, Univ. Limoges, Faculty of Pharmacy, 2 rue du Dr Marcland, F-87025, Limoges, France; Regional Centre for Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky̿ University, Olomouc, Czech Republic.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chantemargue
authors.affiliation: Regional Centre for Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky̿ University, Olomouc, Czech Republic.
authors.forename: Markéta
authors.initials: M
authors.lastname: Paloncýová
authors.affiliation: INSERM UMR 850, Univ. Limoges, Faculty of Pharmacy, 2 rue du Dr Marcland, F-87025, Limoges, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
authors.affiliation: Regional Centre for Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky̿ University, Olomouc, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Otyepka
authors.affiliation: INSERM UMR 850, Univ. Limoges, Faculty of Pharmacy, 2 rue du Dr Marcland, F-87025, Limoges, France; Regional Centre for Advanced Technologies and Materials, Department of Physical Chemistry, Faculty of Science, Palacky̿ University, Olomouc, Czech Republic. Electronic address: patrick.trouillas@unilim.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Trouillas
mesh_terms: D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism*; D003198:Computer Simulation; D003593:Cytoplasm / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D008051:Lipid Bilayers; D008565:Membrane Proteins; D004364:Pharmaceutical Preparations
keywords: Active transport; Drug-membrane interactions; In silico models; Lipid bilayer membranes; Molecular dynamics; Passive permeation