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.     

Molecular modeling of oligopeptide adsorption onto functionalized quartz surfaces

The adsorption of an EAK 16-II oligopeptide sequence in aqueous medium onto functionalized quartz surfaces has been studied by using force field calculations and molecular dynamics methods. Two different surfaces have been simulated respectively involving fully methylated and fully silanolic quartz surfaces. Geometry optimization and molecular dynamics simulations showed that the adsorption process is mainly governed by the electrostatic interactions between SiO- surface groups and the charged residues of the oligopeptide sequence. In particular, it was found that strong electrostatic interactions (a) prompt the parallel orientation of the oligopeptide with respect to the hydrophilic charged surface, resulting in an effective physisorption process and (b) stabilize the beta-sheet configuration of the physisorbed molecules. In particular, the end-on oligopeptide orientations are demonstrated to progressively lie back onto the hydrophilic surface, but this does not happen onto the hydrophobic surface. In any case, no physisorption process was observed for the fully methylated surface, where the molecule is seen to move away from the surface during the simulation time.     

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.     

Effects of ethylene polymerization conditions on the activity of SiO2-supported zirconocene and on polymer properties

The effects of polymerization conditions were evaluated on the production of polyethylene by silica-supported (n-BuCp)₂ZrCl₂ grafted under optimized conditions and cocatalyzed by methylaluminoxane (MAO). The Al : Zr molar ratio, reaction temperature, monomer pressure, and the age and concentration of the catalyst were systematically varied. Most reactions were performed in toluene. Hexane, with the addition of triisobutilaluminum (TIBA) to MAO, was also tested as a polymerization solvent for both homogeneous and heterogeneous catalyst systems. Polymerization reactions in hexane showed their highest activities with MAO : TIBA ratios of 3 : 1 and 1 : 1 for the homogeneous and supported systems, respectively. Catalyst activity increased continuously as Al : Zr molar ratios increased from 0 to 2000, and remained constant up to 5000. The highest activity was observed at 333 K. High monomer pressures (≈ 4 atm) appeared to stabilize active species during polymerization, producing polyethylenes with high molecular weight (≈ 3 × 10⁵ g mol⁻¹). Catalyst concentration had no significant effect on polymerization activity or polymer properties. Catalyst aging under inert atmosphere was evaluated over 6 months; a pronounced reduction in catalyst activity [from 20 to 13 × 10⁵ g PE (mol Zr h)⁻¹] was observed only after the first two days following preparation. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1987–1996, 1999     

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     

Motorcycle brake squeal: experimental and numerical investigation on a case study

Since, nowadays, the NVH performance of a vehicle is one of the most important priorities for the market, the noise radiating from disc brakes is considered a source of considerable discomfort and customer dissatisfaction. Squeal is an example of noise, caused by vibrations induced by friction forces, in which the vibration modes of the brake disc are coupled to those of the friction pads or of the caliper. In this work a case study, in which the squeal phenomenon was detected after changing the supplier of the disc pads, is presented. A test bench was purposely developed to investigate the squeal phenomenon; tests at different rotating speeds and pressures in the brake circuit were carried out employing different friction pads. The experimental apparatus appeared capable of reproducing the phenomenon observed in real practice and to investigate the effect of operating parameters and different components on the onset of instability. Friction tests and geometric analysis of the friction pads were also carried out to complete the investigation. At the same time, a finite element (FE) complex eigenvalue parametric analysis was performed on the brake assembly. The different propensity of the pads to squeal was attributed to differences in their geometry and in their friction coefficients. The FE analysis, confirmed the experimental observations and indicated possible design improvements to increase the stability of the system.     

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.