Towards predictable transmembrane transport: QSAR analysis of anion binding and transport
authors Busschaert, N; Bradberry, SJ; Wenzel, M; Haynes, CJE; Hiscock, JR; Kirby, IL; Karagiannidis, LE; Moore, SJ; Wells, NJ; Herniman, J; Langley, GJ; Horton, PN; Light, ME; Marques, I; Costa, PJ; Felix, V; Frey, JG; Gale, PA
nationality International
journal CHEMICAL SCIENCE
keywords CHLORIDE TRANSPORT; MEMBRANE TRANSPORTERS; CELL-MEMBRANES; FLIP-FLOP; RECEPTORS; VESICLE; RECOGNITION; PRODIGIOSINS; COEFFICIENTS; PARAMETERS
abstract The transport of anions across biological membranes by small molecules is a growing research field due to the potential therapeutic benefits of these compounds. However, little is known about the exact mechanism by which these drug-like molecules work and which molecular features make a good transporter. An extended series of 1-hexyl-3-phenylthioureas were synthesized, fully characterized (NMR, mass spectrometry, IR and single crystal diffraction) and their anion binding and anion transport properties were assessed using H-1 NMR titration techniques and a variety of vesicle-based experiments. Quantitative structure-activity relationship (QSAR) analysis revealed that the anion binding abilities of the mono-thioureas are dominated by the (hydrogen bond) acidity of the thiourea NH function. Furthermore, mathematical models show that the experimental transmembrane anion transport ability is mainly dependent on the lipophilicity of the transporter (partitioning into the membrane), but smaller contributions of molecular size (diffusion) and hydrogen bond acidity (anion binding) were also present. Finally, we provide the first step towards predictable anion transport by employing the QSAR equations to estimate the transmembrane transport ability of four new compounds.
publisher ROYAL SOC CHEMISTRY
issn 2041-6520
year published 2013
volume 4
issue 8
beginning page 3036
ending page 3045
digital object identifier (doi) 10.1039/c3sc51023a
web of science category Chemistry, Multidisciplinary
subject category Chemistry
unique article identifier WOS:000321307000005
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journal impact factor 9.063
5 year journal impact factor 8.757
category normalized journal impact factor percentile 89.766
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