Conductivity spectra of polyphosphazene-based polyelectrolyte multilayers

Polyelectrolyte multilayers are built up from ionically modified polyphosphazenes by layer-by-layer assembly of a cationic (poly[bis(3-amino-N,N,N-trimethyl-1-propanaminium iodide)phosphazene] (PAZ+) and an anionic poly[bis(lithium carboxylatophenoxy)phosphazene] (PAZ-). In comparison, multilayers of poly(sodium 4-styrenesulfonate) (PSS) and poly(allylamine hydrochloride) (PAH) are investigated. Frequency-dependent conductivity spectra are taken in sandwich geometry at controlled relative humidity. Conductivity spectra of ion-conducting materials generally display a dc plateau at low frequencies and a dispersive regime at higher frequencies. In the present case, the dispersive regime shows a frequency dependence, which is deviating from the typical behavior found in most ion-conducting materials. Dc conductivity values, which can be attributed to long-range ionic transport, are on the order of sigmadc = 10-10-10-7 S.cm-1 and strongly depend on relative humidity. For PAZ+/PAZ- multilayers sigmadc is consistently larger by one decade as compared to PSS/PAH layers, while the humidity dependence is similar, pointing at general mechanisms. A general law of a linear dependence of log(sigmadc) on relative humidity is found over a wide range of humidity and holds for both multilayer systems. This very strong dependence was attributed to variations of the ion mobility with water content, since the water content itself is not drastically dependent on humidity.     

Mechanisms of antibiotic resistance: QM/MM modeling of the acylation reaction of a class A beta-lactamase with benzylpenicillin

Understanding the mechanisms by which beta-lactamases destroy beta-lactam antibiotics is potentially vital in developing effective therapies to overcome bacterial antibiotic resistance. Class A beta-lactamases are the most important and common type of these enzymes. A key process in the reaction mechanism of class A beta-lactamases is the acylation of the active site serine by the antibiotic. We have modeled the complete mechanism of acylation with benzylpenicillin, using a combined quantum mechanical and molecular mechanical (QM/MM) method (B3LYP/6-31G+(d)//AM1-CHARMM22). All active site residues directly involved in the reaction, and the substrate, were treated at the QM level, with reaction energies calculated at the hybrid density functional (B3LYP/6-31+Gd) level. Structures and interactions with the protein were modeled by the AM1-CHARMM22 QM/MM approach. Alternative reaction coordinates and mechanisms have been tested by calculating a number of potential energy surfaces for each step of the acylation mechanism. The results support a mechanism in which Glu166 acts as the general base. Glu166 deprotonates an intervening conserved water molecule, which in turn activates Ser70 for nucleophilic attack on the antibiotic. This formation of the tetrahedral intermediate is calculated to have the highest barrier of the chemical steps in acylation. Subsequently, the acylenzyme is formed with Ser130 as the proton donor to the antibiotic thiazolidine ring, and Lys73 as a proton shuttle residue. The presented mechanism is both structurally and energetically consistent with experimental data. The QM/MM energy barrier (B3LYP/ 6-31G+(d)//AM1-CHARMM22) for the enzymatic reaction of 9 kcal mol(-1) is consistent with the experimental activation energy of about 12 kcal mol(-1). The effects of essential catalytic residues have been investigated by decomposition analysis. The results demonstrate the importance of the "oxyanion hole" in stabilizing the transition state and the tetrahedral intermediate. In addition, Asn132 and a number of charged residues in the active site have been identified as being central to the stabilizing effect of the enzyme. These results will be potentially useful in the development of stable beta-lactam antibiotics and for the design of new inhibitors.     

Conformational analyses on histamine H2-receptor antagonists

Summary In a series of compounds with H₂-antihistaminic activity, a conformational analysis was performed based on force field calculations. The drugs studied were cimetidine, ranitidine, famotidine, roxatidine and the conformationally more restricted ICI127032. For the compounds containing a flexible chain, the local minima conformations and the global minimum conformation were calculated. These conformations were used for a systematic structural comparison with all energetically allowed conformations of the ICI derivative, with regard to the best fit of the common structural features. In this way a pharmacophore could be developed consisting of four parts: (1) a polar planar group, uncharged at physiological pH; (2) a hydrophobic part formed by aromatic systems or flexible chains; (3) an—under physiological conditions—protonated nitrogen atom; and (4) a substructure, which contains a hydrogen bond donor site and a hydrogen bond acceptor site in a specific spatial arrangement.     

Surface modification of FePO4 particles with conductive layer of polypyrrole

Polypyrrole–FePO₄ powder was synthesized by an oxidative polymerization of pyrrole monomer on the surface of FePO₄ powder. The polymerization reaction was initiated using hydrogen peroxide in an acidified solution and catalysed with Fe³⁺. The samples were investigated by light microscopy (LM), scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDX). These methods confirmed the presence of polypyrrole on FePO₄ particles and its homogeneous distribution in the composite material. To determine the PPy content in the PPy–FePO₄ composites a thermogravimetric analysis was used. Cyclic voltammetry curves (CV) were measured and compared in a non-aqueous lithium salt solution for electrodes consisting of pellets made from pure FePO4 and FePO₄/PPy. Electrochemical impedance spectroscopy (EIS) showed that coating of PPy significantly decreases the charge transfer resistance of PPy–FePO₄ electrodes.     

Molecular modelling studies on the ORL1-receptor and ORL1-agonists

The ORLI (opioid receptor like 1)- receptor is a member of the family of rhodopsin-like G protein-coupled receptors (GPCR) and represents an interesting new therapeutical target since it is involved in a variety of biomedical important processes, such as anxiety, nociception, feeding, and memory. In order to shed light on the molecular basis of the interactions of the GPCR with its ligands, the receptor protein and a dataset of specific agonists were examined using molecular modelling methods. For that purpose, the conformational space of a very potent non-peptide ORL1-receptor agonist (Ro 64-6198) with a small number of rotatable bonds was analysed in order to derive a pharmacophoric arrangement. The conformational analyses yielded a conformation that served as template for the superposition of a set of related analogues. Structural superposition was achieved by employing the program FlexS. Using the experimental binding data and the superposition of the ligands, a 3D-QSAR analysis applying the GRID/GOLPE method was carried out. After the ligand-based modelling approach, a 3D model of the ORL1-receptor has been constructed using homology modelling methods based on the crystal structure of bovine rhodopsin. A representative structure of the model taken from molecular dynamics simulations was used for a manual docking procedure. Asp-130 and Thr-305 within the ORL1-receptor model served as important hydrophilic interaction partners. Furthermore, a hydrophobic cavity was identified stabilizing the agonists within their binding site. The manual docking results were supported using FlexX, which identified the same protein-ligand interaction points.     

The future of post-genomic biology at the proteomic level: an outlook

Drug discovery and early-stage drugs and biomarkers development is a continuous adaptation and maturation process. The cycle of changes based on new findings is coupled with shifts in research priorities and make this part of pharmaceutical research a challenging endeavour. Over the last years, the emphasis on genomics has shifted to proteomics, the science of understanding how proteins translate gene information into function, and metabonomics, the science of small metabolites that are further apart from genomic projects. Proteomics describes the analysis of the protein complement of a biological sample with respect to temporal and spatial resolution. This technology is based on separation of complex protein mixtures by 2D gel-electrophoresis, in gel digest and mass spectrometric analysis of the protein fragments. Proteomics has been recently flanked by peptidomics, a new research direction aimed at the comprehensive analysis of small (1-20 kDa) polypeptides, thus covering the gap between proteomics and metabonomics. The refinement of peptidomics is based on an essential paradigm related to modularity and diversity. Peptides are a paramount example of how one single gene can release multiple functionalities. We can expect fast progress in understanding protein and peptide networks from a systems biology approach ending in the discovery of new peptide targets. However, the way from a complex sample to potential diagnostic and therapeutic targets will depend on technological developments and from the ability to discriminate true disease-related signals from false positive and negative signals, and the way from target discovery to target validation will not be short.     

Chromophore Systeme, 2. Konformation und Lichtabsorption von (2-Alkoxyvinyl)ethandionen

Chromophoric Systems, 2. – Conformation and Absorption of Light in (2-Alkoxyvinyl)ethanediones The unusual color properties of yellow 1,2-bis(4,5-dihydrofuran-3-yl)ethane-1,2-dione ( 1 ) and colorless 1,2-bis(5,6-dihydro-4H-pyran-3-yl)ethane-1,2-dione ( 2 ) in the solid state and in solution are investigated by crystal structure analysis, UV-Vis, PE, and ¹³C-NMR spectroscopy as well as by reparameterized force-field calculations. Dione 1 takes an antiperiplaner CO/CO conformation of its chromophore in the solid state whereas dione 2 is twisted in this respect by 102°. In solution both chromophores are not planar, but 1 is less distorted (ca. 142°) than dione 2 (ca. 126°). The calculated rotational barrier for CO/CO twisting amounts to 0.9 kcal mol⁻¹ for 1 and to 2.2 kcal mol⁻¹ for 2 .