Tuesday, October 25, 2011

Combating mood disorders: New approach simplifies the search for more specific drugs

Many psychiatric conditions are caused by aberrant metabolism of the neurotransmitter serotonin. Researchers in the Department of Pharmacy at LMU have now developed a new screening method, which will facilitate the search for new drugs that modulate the biological activity of serotonin.

Psychiatric ailments such as depression, obsessive-compulsive disorder or anxiety states are often associated with disturbances in the metabolism of the . Neurotransmitters are compounds that are released from the synapses at nerve cell endings and activate the firing of neighboring neurons. Thus, as their name suggests, they mediate the transmission of nerve impulses. The (SERT) is responsible for reuptake of the transmitter into neurons, terminating its action. SERT is a major for drugs that are used to treat many , and the search for new SERT inhibitors is of continuing therapeutic relevance. A research team led by Professor Klaus Wanner of the Department of Pharmacy in the Center for at Ludwig-Maximilians Univeristät München (LMU) has now developed a novel binding assay, based on the use of mass spectrometry (MS), which promises to simplify the search for potential SERT inhibitors very significantly. The major advantage of the technique is that, unlike conventional binding assays, it avoids the need to use radiolabeled substances. A paper that describes the new assay will appear in the journal ChemMedChem on 4. October. The article has been rated as a "very important paper" and is featured on the cover of the upcoming issue of the journal.

To be effective, most drugs must bind selectively to defined molecular targets in the body. The target may be an enzyme found in certain cells or a protein on the plasma membrane of a specific cell type. Drug candidates must therefore be assessed for their affinity for the target by means of binding assays. These assays often involve the use of a chemical that is already known to recognize and bind selectively to the target as. The ability of a test substance to find and interact with the target is then measured in terms of how well it competes with this "marker" ligand. The greater its ability to displace the marker from the binding site, the higher is its own affinity for the target, and the more likely it is to be clinically effective. In the MS-based binding assay developed by Wanner's group, quantification of the marker is carried out using mass spectrometry. In contrast to conventional techniques, which employ radiolabeled ligands, MS binding assays do not require the use of markers containing radioactive isotopes. This means that the marker can be assayed in its unaltered, native state. "This label-free technique provides all the advantages offered by classical binding studies, while avoiding the need to work with radioactive compounds," explains Wanner. His team has now validated the MS-based binding assay for use in the search for new inhibitors of SERT function. "Because SERT regulates the concentration of serotonin in the synaptic cleft, the protein serves as the major target for the treatment of depression, obsessive-compulsive disorders and anxiety states," says Wanner. Using the well-known antidepressant (S)-fluoxetine as a native marker, his group has now shown that the results of the MS-based assay are in very good agreement with those obtained using radiolabeled ligands. Indeed, the team now routinely uses the MS method to screen for novel, pharmacologically active SERT inhibitors. In addition, Wanner has plans to adapt the approach for use with other target molecules of clinical interest. (göd)

More information: (S)- and (R)-Fluoxetine as Native Markers in Mass Spectrometry (MS) Binding Assays Addressing the Serotonin Transporter.
M. Hess, G. Höfner, K. Wanner. ChemMedChem 2011, vol 6, no. 10, 4. October; First published online 26. July 2011 doi:10.1002/cmdc.201100251

Provided by Ludwig-Maximilians-Universität M?nchen

Study sheds light on the mysterious structure of water-air interface

Findings by Japanese researchers at the RIKEN Advanced Science Institute and their colleagues at Tohoku University and in the Netherlands have resolved a long-standing debate over the structure of water molecules at the water surface. Published in the Journal of the American Chemical Society, the research combines theoretical and experimental techniques to pinpoint, for the first time, the origin of water's unique surface properties in the interaction of water pairs at the air-water interface.

The most abundant compound on the Earth's surface, water is essential to life and has shaped the course of human civilization. As perhaps the most common liquid interface, the air-water interface offers insights into the surface properties of water in everything from atmospheric and environmental chemistry, to , to regenerative medicine. Yet despite its ubiquity, the structure of this interface has remained shrouded in mystery.

At the heart of this mystery are two broad bands in the vibrational spectrum for surface water resembling those of bulk ice and . Whether these bands are the result of hydrogen bonds themselves, of intra-molecular coupling between within a single water molecule, or of inter-molecular coupling between adjacent , is a source of heated debate. One popular but controversial hypothesis suggests one of the spectral bands corresponds to water forming an actual tetrahedral "ice-like" structure at the surface, but this interpretation raises issues of its own.

Study sheds light on the mysterious structure of water-air interface

This is a snapshot in the MD simulation trajectory of the HOD / D2O mixture that shows the water pair at the surface. White, green and red represent H, D and O atoms, respectively. Credit: RIKEN

The researchers set out to resolve this debate through a comprehensive study combining theory and experiment. For their experiments, they applied a powerful spectroscopy technique developed at RIKEN to selectively pick out and rapidly measure their spectra. To eliminate coupling effects, which are difficult to reproduce in simulations, they used water diluted with D2O () and HOD (water with one hydrogen atom, H, replaced by deuterium, D). Doing so eliminates coupling of OH bonds within a single molecule (since there is only one OH bond) and reduces the overall concentration of OH bonds in the solution, suppressing intermolecular coupling.

With other influences removed, the researchers at last pinpointed the source of water's unique surface structure not in an "ice-like" structure, but in the strong hydrogen bonding between water pairs at the outermost surface. The extremely good match between experimental and theoretical results confirms this conclusion, at long last bringing clarity to the debate over the structure of the water surface and setting the groundwork for fundamental advances in a range of scientific fields.

Provided by RIKEN (news : web)

Scientists develop the most advanced computer model to-date of the scattering of polarized light from chiral molecules

An international research team has described the first calculations of Raman optical activity (ROA) spectra using coupled-cluster theory – one of the most reliable quantum chemical methods available. ROA is a valuable tool for the structural characterization of a wide range of molecules, including large biomolecules such as viruses and proteins for which the technique holds a particular prominence.

“We have developed the most advanced computer model to-date of the of from chiral molecules”, says T. Daniel Crawford, researcher at Virginia Tech (USA), who carried out the simulations together with Kenneth Ruud of the University of Tromso (Norway). Chirality – or handedness – is a very important property in chemistry. The new results are presented in the journal ChemPhysChem.

A long-term goal of this area of research is to enable laboratory chemists to carry out their own simulations to study compounds ranging from small molecules to pharmaceuticals and viruses. “This will allow them to identify which ‘hand’ of the compound reacts in a desired way –from providing a certain scent to fighting tumors”, Crawford says. He points out that the model developed by him and his Norwegian colleague is capable of providing predictions of many molecular properties that equal –and sometimes exceed– the accuracy of even the best available experiments. Besides describing the fundamental theoretical aspects of the coupled-cluster functions used in the calculation of ROA , Crawford and Ruud have demonstrated the effectiveness of their method through benchmark computations on (S)-methyloxirane –a compound for which experimental gas-phase data are available. Such rare experimental data, which are free of perturbative solvent effects, provide an excellent testing ground for advanced quantum-chemical methods.

According to the researchers, their future work will focus on more systematic comparisons between coupled-cluster ROA spectra and both density functional theory (DFT) and experiment, including more molecular examples. “Ultimately, we and the world's other quantum chemists seek to carry out ‘computational experiments’ that will provide reliable data more quickly, more safely, and with less expense than laboratory analyses”, Crawford adds.

More information: Daniel Crawford, Coupled-Cluster Calculations of Vibrational Raman Optical Activity Spectra, ChemPhysChem, Permalink to the article: http://dx.doi.org/ … hc.201100547

Provided by Wiley (news : web)

Ionic liquid catalyst helps turn emissions into fuel

An Illinois research team has succeeded in overcoming one major obstacle to a promising technology that simultaneously reduces atmospheric carbon dioxide and produces fuel.

University of Illinois chemical and biomolecular engineering professor Paul Kenis and his research group joined forces with researchers at Dioxide Materials, a , to produce a catalyst that improves . The company, in the university Research Park, was founded by retired chemical engineering professor Richard Masel. The team reported their results in the journal Science.

Artificial photosynthesis is the process of converting into useful carbon-based chemicals, most notably fuel or other compounds usually derived from petroleum, as an alternative to extracting them from .

In plants, photosynthesis uses solar energy to convert carbon dioxide (CO2) and water to sugars and other hydrocarbons. Biofuels are refined from sugars extracted from crops such as corn. However, in artificial photosynthesis, an electrochemical cell uses energy from a or a wind turbine to convert CO2 to simple carbon fuels such as formic acid or methanol, which are further refined to make ethanol and other fuels.

"The key advantage is that there is no competition with the food supply," said Masel, a co-principal investigator of the paper and CEO of Dioxide Materials, "and it is a lot cheaper to transmit electricity than it is to ship biomass to a refinery."

However, one big hurdle has kept artificial photosynthesis from vaulting into the mainstream: The first step to making fuel, turning into carbon monoxide, is too energy intensive. It requires so much electricity to drive this first reaction that more energy is used to produce the fuel than can be stored in the fuel.

The Illinois group used a novel approach involving an ionic liquid to catalyze the reaction, greatly reducing the energy required to drive the process. The ionic liquids stabilize the intermediates in the reaction so that less electricity is needed to complete the conversion.

The researchers used an as a flow reactor, separating the gaseous CO2 input and oxygen output from the liquid electrolyte catalyst with gas-diffusion electrodes. The cell design allowed the researchers to fine-tune the composition of the electrolyte stream to improve reaction kinetics, including adding ionic liquids as a co-catalyst.

"It lowers the overpotential for CO2 reduction tremendously," said Kenis, who is also a professor of mechanical science and engineering and affiliated with the Beckman Institute for Advanced Science and Technology. "Therefore, a much lower potential has to be applied. Applying a much lower potential corresponds to consuming less energy to drive the process."

Next, the researchers hope to tackle the problem of throughput. To make their technology useful for commercial applications, they need to speed up the reaction and maximize conversion.

"More work is needed, but this research brings us a significant step closer to reducing our dependence on fossil fuels while simultaneously reducing CO2 emissions that are linked to unwanted climate change," Kenis said.

More information: The paper, "Ionic Liquid–Mediated Selective Conversion of CO2 to CO at Low Overpotentials," is available online at http://www.science … ence.1209786

Provided by University of Illinois at Urbana-Champaign (news : web)

Synthetic cells: Ion exchange leads to complex cell systems with inorganic membranes

 Our body consists of individual organs that are made of cells, which in turn contain a number of separate organelles. Biological function cannot be maintained if there are no separate compartments, and compartments are also of use in chemistry. In the journal Angewandte Chemie, a team led by Leroy Cronin at the University of Glasgow (UK) has now introduced a method for the easy production of inorganic chemical cells, known as iCHELLS. Their method even makes it possible to make cells embedded within cells.

Membranes for synthetic compartments are normally made from high-molecular-weight polymers by on a surface. In contrast, the iCHELL membranes are made from low-molecular-weight building blocks at the interface of two aqueous solutions. One is simply injected into a second. Solution 1 contains polyoxometallate clusters, tiny “clumps” made of several transition metal atoms, oxygen atoms, and sometimes others. For example, the researchers used a phosphotungstate, a negatively charged in which a phosphorus atom is surrounded by twelve tungsten and 40 oxygen atoms. The counterions are small positively charged ions, such as protons or sodium ions.

Solution 2 contains a compound made of large positively charged organic ions, for example aromatic ring systems, and small negatively charged counterions. When the two solutions come into contact, the ion pairs immediately undergo an exchange of partners: While the two small partners stay in solution, the two large ions come together and aggregate to form a thin membrane because they become insoluble when paired. This forms a cell enclosed by a membrane.

Choosing different ions allows for the thickness and permeability of the membrane to be varied. The membrane can also be given functionality. For example, it is possible to select that catalyze chemical reactions or recognize specific target molecules. The use of microfluidic systems (chips with tiny fluid-filled channels) makes it possible to easily produce the cells in large numbers, which is a prerequisite for technical applications. Potential uses include encapsulated catalysts in which the membrane would selectively allow the substrate to enter the cell to react.

More complex cell systems can also be made: Simply injecting another solution containing a suitable ion into a cell produces a “cell within a cell”. Such systems could be used as vessels for multistep reactions. However, the biggest goal is the formation of synthetic chemical cells with properties that resemble those of living systems. The scientists hope to gain some indication of how life was able to develop in an inorganic world billions of years ago, and whether it is possible to use the iCHELLS as a platform to develop non-organic “inorganic biology” in the laboratory.

More information: Leroy Cronin, Modular Redox-Active Inorganic Chemical Cells: iCHELLs, Angewandte Chemie International Edition, http://dx.doi.org/ … ie.201105068

Provided by Wiley (news : web)