Structure-based approach for identification of novel phenylboronic acids as serine-β-lactamase inhibitors

β-Lactamases are bacterial enzymes conferring resistance to β-lactam antibiotics in clinically-relevant pathogens, and represent relevant drug targets. Recently, the identification of new boronic acids (i.e. RPX7009) paved the way to the clinical application of these molecules as potential drugs. Here, we screened in silico a library of ~1400 boronic acids as potential AmpC β-lactamase inhibitors. Six of the most promising candidates were evaluated in biochemical assays leading to the identification of potent inhibitors of clinically-relevant β-lactamases like AmpC, KPC-2 and CTX-M-15. One of the selected compounds showed nanomolar K _i value with the clinically-relevant KPC-2 carbapenemase, while another one exhibited broad spectrum inhibition, being also active on Enterobacter AmpC and the OXA-48 class D carbapenemase.     

Practical aspects of chemometrics for oil spill fingerprinting

Tiered approaches for oil spill fingerprinting have evolved rapidly since the 1990s. Chemometrics provides a large number of tools for pattern recognition, calibration and classification that can increase the speed and the objectivity of the analysis and allow for more extensive use of the available data in this field. However, although the chemometric literature is extensive, it does not focus on practical issues that are relevant to oil spill fingerprinting. The aim of this review is to provide a framework for the use of chemometric approaches in tiered oil spill fingerprinting and to provide clear-cut practical details and experiences that can be used by the forensic chemist. The framework is based on methods for initial screening, which include classification of samples into oil type, detection of non matches and of weathering state, and detailed oil spill fingerprinting, in which a more rigorous matching of an oil spill sample to suspected source oils is obtained. This review is intended as a tutorial, and is based on two examples of initial screening using respectively gas chromatography with flame ionization detection and fluorescence spectroscopy; and two of detailed oil spill fingerprinting where gas chromatography-mass spectrometry data are analyzed according to two approaches: The first relying on sections of processed chromatograms and the second on diagnostic ratios.     

Insights into docking and scoring neuronal α4β2 nicotinic receptor agonists using molecular dynamics simulations and QM/MM calculations

A combined quantum mechanical (QM)‐polarized docking and molecular dynamics approach to study the binding mode and to predict the binding affinity of ligands acting at the α4β2‐nAChR is presented. The results obtained in this study indicate that the quantum mechanical/molecular mechanics docking protocol well describes the charge‐driven interactions occurring in the binding of nicotinic agonists, and it is able to represent the polarization effects on the ligand exerted by the surrounding atoms of the receptor at the binding site. This makes it possible to properly score agonists of α4β2‐nAChR and to reproduce the experimental binding affinity data with good accuracy, within a mean error of 2.2 kcal/mol. Moreover, applying the QM‐polarized docking to an ensemble of nAChR conformations obtained from MD simulations enabled us to accurately capture nAChR‐ligand induced‐fit effects. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

Quantification of p-cresol sulphate in human plasma by selected reaction monitoring

Chronic renal failure patients accumulate in the blood molecules that are normally excreted into the urine. p-Cresol Sulphate (pCS), the most representative retained toxin, shows a high level of toxicity. Therefore, its quantification could represent a prediction factor to determine the risk of endothelial dysfunction and cardiovascular complication and response to the haemodialysis treatment. The aim of this study was to evaluate the suitability of the multiple reaction monitoring (MRM) technique in order to improve the sensibility, the selectivity and the timing of pCS detection in a small amount of plasma. Deproteinized plasma of uremic patients was concentrated and dissolved in liquid chromatography (LC) mobile phase solution. pCS was quantified by LC coupled to tandem mass spectrometry (LC-MS/MS) on a triple-quadrupole mass spectrometer. Selective and sensitive detection of pCS was achieved by selecting the specific parent ion and monitoring two specific fragment ions. The MRM assay was carried out using the following transitions: m/z 187?→?80.00 and m/z 187?→?107.00. A good linearity was observed for each calibration curve. The intra-day and inter-day results showed a good precision and repeatability. The percentage recoveries indicate an optimal selectivity of the analytical method. The MRM assay to quantify pCS in a small amount of human plasma is rapid, highly sensitive, selective and with a good repeatability.     

Weak localization of light in superdiffusive random systems

Lévy flights constitute a broad class of random walks that occur in many fields of research, from biology to economy and geophysics. The recent advent of Lévy glasses allows us to study Lévy flights-and the resultant superdiffusion-using light waves. This raises several questions about the influence of interference on superdiffusive transport. Superdiffusive structures have the extraordinary property that all points are connected via direct jumps, which is expected to have a strong impact on interference effects such as weak and strong localization. Here we report on the experimental observation of weak localization in Lévy glasses and compare our results with a recently developed theory for multiple scattering in superdiffusive media. Experimental results are in good agreement with theory and allow us to unveil the light propagation inside a finite-size superdiffusive system.     

Programming scale-free optics in disordered ferroelectrics

Using the history dependence of a dipolar glass hosted in a compositionally disordered lithium-enriched potassium tantalate niobate (KTN:Li) crystal, we demonstrate scale-free optical propagation at tunable temperatures. The operating equilibration temperature is determined by previous crystal spiralling in the temperature/cooling-rate phase space.     

SiO2-B2O3 xerogels: The problem of boron leaching

Borosilicate materials are of interest for many technological applications. Whereas sol-gel techniques are well suited for the preparation of these materials, the nominal concentration of boron is often not maintained, and a considerable amount of boron is lost during the preparation procedure. In this work we deal with the synthesis of borosilicate systems in order to analyse the problem of the boron loss. Different sol-gel precursors of B₂O₃ were explored and organically modified silicon alcoxide were tested, in addition P₂O₅ co-doping was proposed. IR spectroscopy, differential Scanning Calorimetry, Thermogravimetry and ICP-OES analyses were performed. Sol-gel synthesis of SiO₂-B₂O₃ xerogels with a high boron content (> 18 wt.%) was successfully obtained by employing trimethoxyboroxine and 3-aminopropyltriethoxysilane.     

Intramolecular and intermolecular OH…O and OH…F interactions in perfluoropolyethers with polar end groups: IR spectroscopy and first-principles calculations

Perfluoropolyether (PFPE) fluids constitute a class of polymers that fulfil a wide range of requirements for hi-tech applications, due to their pefluorinated backbone. For some of these applications they are requested to bear polar end groups, and the combination of a chemical inert backbone and a reactive end group can produce peculiar conformations and supramolecular structures. The molecular structure and the vibrational properties of the ethoxyl-terminated PFPE FLUOROLINK®E10H in solution are here investigated by means of IR spectroscopy. It is shown that the complex spectral features of the OH-stretching region cannot be explained without a thorough computational study, involving the investigation of the conformational space of an isolated model molecule by means of semiempirical AM1 calculations and DFT calculations. The most relevant conformers were singled out, showing a high degree of conformational disorder for FLUOROLINK®E10H. Furthermore, it is shown that intra- and intermolecular H-bonding affects significantly the molecular structure and the vibrational spectrum. Several interactions are shown to be relevant, such as OH^…F interactions and complexes with residual water. Theoretical values of the absolute intensities of OH stretching IR bands, relevant for the analytical applications, are obtained.     

Glycine and alanine: a theoretical study of solvent effects upon energetics and molecular response properties

In the present work, we show that polarisable continuum model is able to reproduce the stability of zwitterionic forms of amino acids alanine and glycine in water solution at B3-LYP/6-31G (d) level of theory. The model is then extended to the calculation of vibrational frequencies, Vibrational circular dichroism spectra and nuclear magnetic resonance chemical shifts. The agreement with experimental data is good, except in the case of vibrations where specific hydrogen bond interactions are involved. In the latter case, a supermolecular approach may help in the predictions of some vibrational frequencies of the groups which form hydrogen bonds.     

Chemical and Mechanical Characterization of Licorice Root and Palm Leaf Waste Incorporated into Poly(urethane-acrylate) (PUA)

A poly(urethane-acrylate) polymer (PUA) was synthesized, and a sufficiently high molecular weight starting from urethane-acrylate oligomer (UAO) was obtained. PUA was then loaded with two types of powdered ligno-cellulosic waste, namely from licorice root and palm leaf, in amounts of 1, 5 and 10%, and the obtained composites were chemically and mechanically characterized. FTIR analysis of final PUA synthesized used for the composite production confirmed the new bonds formed during the polymerization process. The degradation temperatures of the two types of waste used were in line with what observed in most common natural fibers with an onset at 270 °C for licorice waste, and at 290 °C for palm leaf one. The former was more abundant in cellulose (44% vs. 12% lignin), whilst the latter was richer in lignin (30% vs. 26% cellulose). In the composites, only a limited reduction of degradation temperature was observed for palm leaf waste addition and some dispersion issues are observed for licorice root, leading to fluctuating results. Tensile performance of the composites indicates some reduction with respect to the pure polymer in terms of tensile strength, though stabilizing between data with 5 and 10% filler. In contrast, Shore A hardness of both composites slightly increases with higher filler content, while in stiffness-driven applications licorice-based composites showed potential due to an increase up to 50% compared to neat PUA. In general terms, the fracture surfaces tend to become rougher with filler introduction, which indicates the need for optimizing interfacial adhesion.