Crystal Structure and Local Dynamics in Tetrahedral Proton-Conducting La1-xBa1+xGaO4

La1-xBa1+xGaO4-0 (LBG) compounds, based on unconnected GaO4 moieties, were recently proposed as proton conductors. Protonic defects in the lattice are inserted through self-doping with Ba2+, to create oxygen vacancies subsequently filled by hydroxyl ions. We present a combined structural analysis on self-doped LBG using X-ray diffraction (XRD) and X-ray absorption (EXAFS): these results unravel the finer structural details on the short-range and long-range scales, and they are correlated with the dynamical properties of protonic conduction coming from vibrational spectroscopy. The structure of the GaO4 groups is independent of the oxide composition. On hydration, an array of short intertetrahedral hydrogen bonds is formed, producing a contraction of the a axis. On the basis of thermogravimetric analysis, EXAFS, XRD and infrared spectroscopy (IR) results, we propose that the stiffness of the GaO4 tetrahedra hinders the intratetrahedral proton transfer, while the noticeable fraction of protons involved in strong hydrogen bonds limit the proton reorientational freedom

Dopants and defects in proton-conducting perovskites

Many doped perovskites show high proton conductivity at intermediate to high temperatures (500- 900 °C), which has opened possibilities for many prospected applications in energy conversion (fuel cells), and electrochemical devices. In a doped perovskite, e.g. BaCe1-xYxO3-y, oxygen vacancies are created by charge compensation, and can eventually react with air moisture to form structural protonic defects. The sluggish nature of the proton, which is practically invisible to most structural analyses, and poses enormous problems to quantum chemistry, has surely contributed to slow down the progress in the understanding of these materials: in fact, the conduction dynamics and its interplay with structure are still matter of debate. The kind of trivalent dopant and its size, and the doping level, have all been found to critically influence the conductivity: to date, however, no comprehensive model was developed, and no clear explanations exist between the chemical and dynamical properties. Here we present results collected in several EXAFS experiments on doped BaCeO3 and BaZrO3 spanning three years, on the Ba site, Ce site, and the dopant (yttrium, gadolinium, indium: the ionic sizes of these are respectively equal, larger and smaller than Ce4+) site. The local structures up to about 6 Å around each site are solved with state-of-the-art techniques employing both the GNXAS and FEFF approaches, revealing unique features and demonstrating that in this case the conventional diffraction techniques are not suited to unravel the complexity of doped crystals. In particular, the attention will be drawn on the local deviations from Vegard’s law, the local expansion/contraction as a function of hydration degree, the interplay between dopant and defects, and the chemical compatibility (Pearson absolute hardness) instead of ionic size matching. The EXAFS results are correlated with complementary information about the dynamics of protons and other defects (IR and neutron vibrational spectroscopy, QENS, ionic and electronic conductivity measurements)

Pharmacophore modelling as useful tool in the lead compounds identification and optimization

The goal of computer-aided molecular design methods in modern medicinal chemistry is to reduce the overall cost and time associated to the discovery and development of a new drug by identifying the most promising candidates to focus the experimental efforts on. Very often, many drug discovery projects have reached already a well-advanced stage before detailed structural data on the protein target have become available. A possible consequence is that often, medicinal chemists develop novel compounds for a target using preliminary structure–activity information, together with the theoretical models of interactions. Only responses that are consistent with the working hypothesis contribute to an evolution of the used models. Within this framework, the pharmacophore approach has proven to be successful, allowing the perception and understanding of key interactions between a receptor and a ligand[1]. In recent years, our research group exploited this useful modeling tool with the aim to identify new chemical entities and/or optimizing known lead compounds to obtain more active drugs in the field of antitumor, antiviral, and antibacterial drugs. In this communication, we present an overview of our recent works in which we used the pharmacophore modelling approach combined with induced fit docking, 3D-QSAR approach, and HTVS for the analysis of drug-receptor interactions and the discovery of new inhibitors of IKKβ, Bcl-xl, and c-kit tyrosine kinase, all targets involved into the initiation and the development of different types of cancer[2-5]

Long-Range and Short-Range Structure of Proton-Conducting Y:BaZrO3

Yttrium-doped barium zirconate (BZY) is the most promising candidate for proton-conducting ceramics and has been extensively studied in recent years. The detailed features of the crystal structure, both short-range and long-range, as well as the crystal chemistry driving the doping process, are largely unknown. We use very high resolution X-ray diffraction (HR-XRD) to resolve the crystal structure, which is very slightly tetragonally distorted in BZY, while the local environment around Zr4+ and Y3+ is probed with extended X-ray absorption fine structure (EXAFS), and the symmetry and vibrations are investigated by using Raman spectroscopy. It is found that barium zirconate shows some degree of local deviation from the cubic arystotype even if undoped, which upon substitution by the perceptibly larger Y3+, playing the role of a rigid inclusion, is further increased. This distortion is one limiting factor concerning the Y3+ solubility. The effects are correlated to the proton conduction properties of BZY

DRUDIT: web-based DRUgs DIscovery Tools to design small molecules as modulators of biological targets.

Abstract Motivation New in silico tools to predict biological affinities for input structures are presented. The tools are implemented in the DRUDIT (DRUgs DIscovery Tools) web service. The DRUDIT biological finder module is based on molecular descriptors that are calculated by the MOLDESTO (MOLecular DEScriptors TOol) software module developed by the same authors, which is able to calculate more than one thousand molecular descriptors. At this stage, DRUDIT includes 250 biological targets, but new external targets can be added. This feature extends the application scope of DRUDIT to several fields. Moreover, two more functions are implemented: the multi- and on/off-target tasks. These tools applied to input structures allow for predicting the polypharmacology and evaluating the collateral effects. Results The applications described in the article show that DRUDIT is able to predict a single biological target, to identify similarities among biological targets, and to discriminate different target isoforms. The main advantages of DRUDIT for the scientific community lie in its ease of use by worldwide scientists and the possibility to be used also without specific, and often expensive, hardware and software. In fact, it is fully accessible through the WWW from any device to perform calculations. Just a click or a tap can start tasks to predict biological properties for new compounds or repurpose drugs, lead compounds, or unsuccessful compounds. To date, DRUDIT is supported by four servers each able to execute 8 jobs simultaneously. Availability and implementation The web service is accessible at the www.drudit.com URL and its use is free of charge. Supplementary information Supplementary data are available at Bioinformatics online

In Silico Design of New Dual Inhibitors of SARS-CoV-2 MPRO through Ligand- and Structure-Based Methods

The viral main protease is one of the most attractive targets among all key enzymes involved in the life cycle of SARS-CoV-2. Considering its mechanism of action, both the catalytic and dimerization regions could represent crucial sites for modulating its activity. Dual-binding the SARS-CoV-2 main protease inhibitors could arrest the replication process of the virus by simultaneously preventing dimerization and proteolytic activity. To this aim, in the present work, we identified two series' of small molecules with a significant affinity for SARS-CoV-2 M-PRO, by a hybrid virtual screening protocol, combining ligand- and structure-based approaches with multivariate statistical analysis. The Biotarget Predictor Tool was used to filter a large in-house structural database and select a set of benzo[b]thiophene and benzo[b]furan derivatives. ADME properties were investigated, and induced fit docking studies were performed to confirm the DRUDIT prediction. Principal component analysis and docking protocol at the SARS-CoV-2 M-PRO dimerization site enable the identification of compounds 1b,c,i,l and 2i,l as promising drug molecules, showing favorable dual binding site affinity on SARS-CoV-2 M-PRO

Hydrocarbons removal from wastewater by adsorption onto biochar from Posidonia oceanica

Environmental pollution by petroleum derivatives is a very current topic. In particular, low concentration of this kind of pollutants can seriously compromise the life of animals and plants of aquatic ecosystems [1]. For this reason, recent environmental legislation imposes severe restriction to oil-in-water content for overboard discharge with concentration limits from 15 to 5 ppm [2]. The shipping industry is trying to adapt to these directives by equipping ships with cleaning treatment devices in which there are several oil removal steps. Usually, the last step of bilge water treatment is based on adsorption onto suitable adsorbent materials that must be able to remove the last and most dispersed oil fraction reducing its concentration within legal limits. In this work, a biochar obtained from pyrolysis of Posidonia oceanica, a Mediterranean sea plant, has been tested as adsorbent material of a synthetic bilge water. The pristine biochar (BCP) was tested as it was and after two chemical activation treatments with sulfuric acid (BCA) and potassium hydroxide (BCB). The adsorbent materials have been characterized by using different techniques (TGA, SEM-EDAX, FT-IR, etc) and their adsorption capacity was studied by batch and column experiments. Oil concentration measurements were performed by using: HPLC-FLD and TOC techniques

Functionalization of a layered oxide with organic moieties: towards hybrid proton conductors

The design of innovative proton conductors for intermediate-temperature fuel cells, closing the gap between PEMFC and SOFC, is a forefront research theme in materials chemistry. [1] Layered perovskites with the Dion-Jacobson structure (ALaNb2O7) have bidimensional lanthanum niobate sheets, separated by a layer of A+ cations. These can be substituted by a variety of molecules with soft chemistry, to yield inorganic-organic hybrids. In particular, the intercalation of amines, alcohols, carboxylic or phosphonic acids, and their covalent binding to the sheets has been demonstrated recently. [2-4]We present preliminary results on the intercalation and covalent bonding of different organic molecules, in order to develop hybrid proton conductors for use in intermediate temperature fuel cells. Smaller molecules (such as alcohols) are intercalated to expand the interlayer space, to form intermediates for the further binding of proton carriers such as imidazoles or sulfonates.The intercalation process is investigated by XRD (to measure the interlayer distance) and TGA (to determine the weight loss upon thermal decomposition). NMR is applied to confirm the covalent bonding between the organic and oxide parts. The intercalation behavior of different functional groups is explained in terms of van der Waals and/or hydrogen bonding between organic chains. The interplay of theory (ab initio and periodic DFT) and experiment allowed us to elucidate the 1H and 13C-NMR spectra, and to investigate the nature of interaction (i.e. ionic or covalent bond) of the organic chains with the interlayer surface

Design and Synthesis of Novel Thieno[3,2-c]quinoline Compounds with Antiproliferative Activity on RET-Dependent Medullary Thyroid Cancer Cells

RET kinase gain-of-function mutations represent the main cause of the high aggressiveness and invasiveness of medullary thyroid cancer (MTC). The selective inhibition of the RET kinase is a suitable strategy for the treatment of this endocrine neoplasia. Herein, we performed an innovative ligand-based virtual screening protocol using the DRUDITonline web service, focusing on the RET kinase as a biological target. In this process, thieno[3,2-c]quinolines 6a-e and 7a-e were proposed as new potential RET inhibitors. The selected compounds were synthetized by appropriate synthetic strategies, and in vitro evaluation of antiproliferative properties conducted on the particularly aggressive MTC cell line TT(C634R) identified compounds 6a-d as promising anticancer agents, with IC50 values in the micromolar range. Further structure-based computational studies revealed a significant capability of the most active compounds to the complex RET tyrosine kinase domain. The interesting antiproliferative results supported by in silico predictions suggest that these compounds may represent a starting point for the development of a new series of small heterocyclic molecules for the treatment of MTC