In silico pharmacology: Drug membrane partitioning and crossing. (September 2016)

• Record Type: Journal Article
• Authors: Di Meo, Florent; Fabre, Gabin; Berka, Karel; Ossman, Tahani; Chantemargue, Benjamin; Paloncýová, Markéta; Marquet, Pierre; Otyepka, Michal; Trouillas, Patrick
• Is Part Of: Pharmacological research. Volume 111(2016:Sep.)
• Page Start: 471
• Page End: 486
• Publication Date: 2016-09
• Subjects: ABC ATP-binding cassette -- ADME absorption, distribution, metabolism and excretion -- AMP antimicrobial peptide -- CG coarse-grained -- COX cyclooxygenase -- CYP cytochrome P450 -- DLiPC dilinoeyl-phosphatidylcholine -- DOPC 1, 2-dioleoyl-sn-glycero-3-phosphocholine -- GA general anesthetic -- GlpT glycerol-3-phosphate:phosphate transporter -- GLUT1 glucose transporter -- GST glutathione S-transferase -- IF inward facing -- LA local anesthetic -- LacY lactose permease -- MATE multi-antimicrobial extrusion protein -- MD molecular dynamics -- MFS major facilitator superfamily -- MM/PBSA molecular mechanics/Poisson-Boltzmann surface area -- MM/GBSA molecular mechanics/generalized born surface area -- Msba bacterial ABC lipid flippase -- NAT N-acetyltransferases -- NBD nucleotide-binding domains -- NSAID non-steroidal anti-inflammatory drug -- NSS neurotransmitter:sodium symporter -- OAT organic anion transporter -- OF outward facing -- PEPT peptide transporter -- PIP2 phosphatidylinositol 4, 5-bisphosphate -- PMF potential of mean force -- POPC 1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphocholine -- POPG 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol -- QM/MM quantum mechanics/molecular mechanics -- SLC solute carrier -- SULT sulfotransferase -- TM transmembrane helice -- TMD transmembrane domain -- UGT uridine 5⿲-diphospho-glucuronosyltransferase -- XylE xylose:H+ symporter; Molecular dynamics -- Lipid bilayer membranes -- Drug-membrane interactions -- Passive permeation -- Active transport -- In silico models; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.06.030
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: 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.