Discovery of Chalcone-Based Hybrid Structures as High Affinity and Site-Specific Inhibitors Against COVID-19; a Study Based on Various Host-Based and Viral Targets

3-Chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are at the forefront of attention for finding therapeutic agents for the treatment of COVID-19. In addition, proper modulation of host-based antiviral targets (HBATs) has also been highlighted by scientists as a promising approach for the suppression of the SARS-CoV-2. Previous studies indicated that some natural-based chalcones have significant inhibitory effect on the coronavirus enzymes 3CLpro and PLpro as well as modulation of some HBATs. In this study, a computational screening was performed to investigate the affinity of our compound library consisting of 757 chalcone-based structures (CHA-1 to CHA-757) for inhibiting the 3CLpro and PLpro enzymes, and also against twelve selected host-based targets. The twelve selected HBATs were chosen based on their involvement in viral reproduction. Our results indicated that CHA-12 (VUF 4819) is the most potent and a multi-target inhibitor in our chemical library over all viral and host-based targets. Correspondingly, CHA-384 and its congeners containing ureide moieties were found to be potent and selective 3CLpro inhibitors, and benzotriazole moiety in CHA-37 was found to be a main fragment for inhibiting the 3CLpro and PLpro. Surprisingly, our results were fully consistent with recent reports on the site-specific 3CLpro inhibitors. The results also indicate that the ureide and sulfonamide moieties are integral fragments for the optimum 3CLpro inhibition while occupying the S1 and S3 subsites. Finding the multi-target inhibitor CHA-12, previously reported as a LTD4 antagonist for the treatment of inflammatory pulmonary diseases, prompted us to suggest it as a concomitant antiviral agent for relieving respiratory symptoms and suppressing COVID-19 infection.

Geophysical search for fragments of the Sterlitamak meteorite

Relevance is determined by the fact that meteorites are of great importance for the direct study of the substance of the Universe, therefore, when new meteorites fall, maximum efforts are made to detect them and study the conditions of the fall. The purpose of the work is to further study the meteorite crater and search for large fragments of the Sterlitamak meteorite not found at the first stage of study using geophysical methods. The story of the fall and searches for the main fragment of the Sterlitamak meteorite, which fell on August 17, 1990 at 23 h 25 min, on the field of the Sterlitamak state farm is described. When it fell, a crater with a diameter of 10 m and a depth of 4 m was formed. The fall was accompanied by a bright glow and thunderous rumbles. A glow was observed over the crater in the dark. A high-speed searching for the meteorite was organized by collecting meteorite debris around the crater. At the same time, a mine detector was used. The crater was excavated with an excavator to a depth of 18–20 m. Fragments weighing 6.6; 3.06; 0.875; 0.363 kg were found. A year later, the main body weighing 315 kg was accidentally found in the dumps. Chemical analysis of the substance showed that it is an iron-nickel meteorite, 98% of the thickness are the minerals kamacite, tenite and schreibersite. Results. In 2014–2015, the authors carried out magnetic surveying around the crater and on the ice of the lake, which was formed at the excavation site, in order to search for fragments of the meteorite, which were probably missed at the initial stage. Maps of the magnetic field and terrain of the crater are given. Magnetic anomalies are identified, which are presumably associated with new fragments of the meteorite. The probable depths of the meteorite fragments are 2–4 m. In-depth sections of the magnetization for these anomalies obtained by the method of magnetic tomography, are given, as well as the results of a surface survey of the dump area using a metal detector. Weakly magnetic samples were found containing sprayed metal and metal balls with a diameter of 0.5–1.0 mm. These samples originally formed a zone of impact metamorphism, which was destroyed by excavation operations. It is shown that the territory is promising for searching for new large fragments of the meteorite and studying the processes of impact metamorphism. It is planned to further study the crater by means of electrical exploration and GPR sounding.

What does the term “documentation” mean

The publication is the main fragment of the report of the Swiss librarian and bibliographer Marcel Gaudet (fr. Marcel Gaudet; 1877, Switzerland – 1949, ibid.) at the Congress of the International Federation for Documentation (FID) 1939, translated by Lubov B. Khavkina, a classic of Russian and Soviet Librarianship. The Piece has a double interest: as rolling pins of your time when the Phenomenon of Documentation, as well as appeared in practice, documentation Centres, only comprehended and discussed, the activity Centers have been criticized, the relationship with the library functions was unclear; and as evidence of close attention to this issue Lubov B. Khavkina, too, only still developing its attitude to the innovation that appeared in the Western World.

VOLUMETRIC EFFECTS FOR IMAGE FORMATION OF 3D ASYMMETRIC EDGE

The peculiarities for formation of the image of volumetric asymmetric absolutely absorbing edge (the main fragment of constant thickness thick plates) in a diffraction-limited projection system are investigated in analytical form applied to 3D-objects dimensional inspection. Structures and profiles of image intensities for front and back object sides are studied respectively at small and big apertures of the 3D-object optical system for various ratios of object bevel c , the Fresnel zone size d ~ ( l - the light wavelength, d - object thickness) and an angular aperture of the optical system. It is shown that in case when the bevel с << d , the shift of intensity profile of the 3D-edge image, proportional to Fresnel's zone and bevel size, takes place. Formulas for the image profile of the back side are obtained and investigated in case of strong volumetric effects, when the focus-row depth of the system is much less than the object thickness. The obtained results are in good agreement with results of computer simulations.

Production of highly oxygenated organic molecules (HOMs) from trace contaminants during isoprene oxidation

During nucleation studies from pure isoprene oxidation in the CLOUD chamber at the European Organization for Nuclear Research (CERN) we observed unexpected ion signals at m∕z = 137.133 (C10H17+) and m∕z = 81.070 (C6H9+) with the recently developed proton-transfer-reaction time-of-flight (PTR3-TOF) mass spectrometer instrument. The mass-to-charge ratios of these ion signals typically correspond to protonated monoterpenes and their main fragment. We identified two origins of these signals: first secondary association reactions of protonated isoprene with isoprene within the PTR3-TOF reaction chamber and secondly [4+2] cycloaddition (Diels–Alder) of isoprene inside the gas bottle which presumably forms the favored monoterpenes limonene and sylvestrene, as known from literature. Under our PTR3-TOF conditions used in 2016 an amount (relative to isoprene) of 2 % is formed within the PTR3-TOF reaction chamber and 1 % is already present in the gas bottle. The presence of unwanted cycloaddition products in the CLOUD chamber impacts the nucleation studies by creating ozonolysis products as the corresponding monoterpenes and is responsible for the majority of the observed highly oxygenated organic molecules (HOMs), which in turn leads to a significant overestimation of both the nucleation rate and the growth rate. In order to study new particle formation (NPF) from pure isoprene oxidation under relevant atmospheric conditions, it is important to improve and assure the quality and purity of the precursor isoprene. This was successfully achieved by cryogenically trapping lower-volatility compounds such as monoterpenes before isoprene was introduced into the CLOUD chamber.

Structural investigation of sparfloxacin drug using mass spec-trometry and MNDO semi-empirical molecular orbital calcu-lations

Sparfloxacin is a broad spectrum antibacterial fluoroquinolone against some microorganisms including gram-positive and gram-negative bacteria and exhibits moderate activity against anaerobes and mycobacteria. Sparfloxacin is well tolerated and the intake of food has no adverse effect on the pharmacokinetic features (Blondeau 1999, Stahlmann et al. 1998). For the medical important of this drug author have been study its structure by recording and investigate its electron ionization (EI) mass spectra at different electron energies 70 and 15 eV. Also, the chemical ionization (CI) mass spectrum has been recorded and investigated. The main fragmentation processes in EI and CI have elucidated and discussed. The main fragment ions in EI mass spectra are [M-C4H8N] + and fragment [M- C4H8N- CO2] +, while [MH- CO2]+ ion are the most fragment ion in CI mass spectrum. On the other hand, the molecular structure optimization of sparfloxacin was calculated using the modified neglect of diatomic overlap (MNDO) semi-empirical molecular orbital method. Also, the thermochemical data such as heat of formations, total energy, ionization energy, electron affinity and dipole moment have been calculated and discussed.

Production of highly oxygenated organic molecules (HOMs) from trace contaminants during isoprene oxidation

During nucleation studies from pure isoprene oxidation in the CLOUD chamber at CERN we observed unexpected ion signals at m/z = 137.133 (C10H17+) and m/z = 81.070 (C6H9+) with the recently developed proton transfer reaction time-of-flight mass spectrometer (PTR3‑TOF) instrument. The mass-to-charge ratios of these ion signals typically correspond to protonated monoterpenes and their main fragment. We identified two origins of these signals: First secondary association reactions of protonated isoprene with isoprene within the PTR3 reaction chamber and secondly [4+2] cycloaddition (Diels-Alder) of isoprene inside the gas bottle which presumably forms the favoured monoterpenes limonene and sylvestrene, as known from literature. Under our PTR3 conditions used in 2016 an amount (relative to isoprene) of 2 % is formed within the PTR3 reaction chamber and 1 % is already present in the gas bottle. The presence of unwanted cycloaddition products in the CLOUD chamber impacts the nucleation studies by creating ozonolysis products as corresponding monoterpenes, and is responsible for the majority of the observed highly oxygenated organic molecules (HOMs). In order to study NPF from pure isoprene oxidation under atmospheric relevant conditions, it is important to improve and assure the quality and purity of the precursor isoprene. This was successfully achieved by cryogenically trapping lower volatility compounds such as monoterpenes before isoprene was introduced into the CLOUD chamber.

Complications of appendicular fracture repair in cats and small dogs using locking compression plates

SummaryObjective: Our objectives were: 1) to review the complications associated with stabilization of appendicular fractures in cats and small dogs using locking compression plates (LCP), and 2) to identify factors that could influence fixation construct stability.Study design: Retrospective clinical study.Materials and methods: Medical and radiographic records of cats and small dogs with appendicular fractures treated with LCP were reviewed. Only cases with adequate follow-up to document clinical union and cases for which complications appeared before the clinical union were included. Complications were classified as implant-related complications or other complications. Cases with implant-related complications were compared to cases with non-implant-related complications for differences in signalment (species, age, body weight, multiple fractures), fracture location and type (fractured bone, fracture localization, closed or open fracture), reduction method (open reduction and internal fixation [ORIF] or minimally invasive plate osteosynthesis [MIPO]) and fixation evaluations (implant size, platebridging ratio, plate span ratio, working length, plate screw density, number of screws and cortices engaged per plate and per main fragment, ratio between screw and bone diameter at the narrowest aspect of the bone, and presence of ancillary fixation).Results: Seventy-five fractures from 63 cats (64 fractures) and 10 dogs (11 fractures) met the inclusion criteria. Eight humeral, 13 radio-ulnar, 26 femoral, and 28 tibio-fibular fractures were treated. Primary repair of the fracture was performed using 2.0 mm and 2.4 mm LCP in 22 and 53 fractures, respectively. Overall and implant-related complications were encountered in 13 and seven of 75 fractures, respectively. Fixation failure was not significantly associated with any aforementioned factor considered in this study, and in particular, there was no significant difference in the occurrence of fixation failure between fractures stabilized with two, or more than two, bicortical locking screws per main fragment.Clinical significance: 2.0 mm and 2.4 mm LCP were used to manage appendicular fractures in cats and small dogs. The overall complication and fixation failure rate were comparable to those reported in previous studies in which various locking plate systems were used.Online Supplementary Material for this article is available at: http://dx.doi.org/10.3415/VCOT-14-09-0146

A polymeric cobalt(II) complex derived from citric acid (H4cit) and 2,6-diaminopurine (dap): {[Co4(cit)2(dap)4(H2O)4]·6.35H2O}n

Poly[[tetraaquadi-μ4-citrato-tetrakis(2,6-diaminopurine)tetracobalt(II)] 6.35-hydrate], {[Co4(C6H4O7)2(C5H6N6)4(H2O)4]·6.35H2O}n, presents three different types of CoIIcations in the asymmetric unit, two of them lying on symmetry elements (one on an inversion centre and the other on a twofold axis). The main fragment is further composed of one fully deprotonated citrate (cit) tetraanion, two 2,6-diaminopurine (dap) molecules and two aqua ligands. The structure is completed by a mixture of fully occupied and disordered solvent water molecules. The two independent dap ligands are neutral and the cit tetraanion provides for charge balance, compensating the 4+ cationic charge. There are two well defined coordination geometries in the structure. The simplest is mononuclear, with the CoIIcation arranged in a regular centrosymmetric octahedral array, coordinated by two aqua ligands, two dap ligands and two O atoms from the β-carboxylate groups of the bridging cit tetraanions. The second, more complex, group is trinuclear, bisected by a twofold axis, with the metal centres coordinated by two cit tetraanions through their α- and β-carboxylate and α-hydroxy groups, and by two dap ligands bridging through one of their pyridine and one of their imidazole N atoms. The resulting coordination geometry around each metal centre is distorted octahedral. Both groups are linked alternately to each other, defining parallel chains along [201], laterally interleaved and well connectedviahydrogen bonding to form a strongly coupled three-dimensional network. The compound presents a novel μ4-κ5O:O,O′:O′,O′′,O′′′:O′′′′ mode of coordination of the cit tetraanion.

Use of aldolases in the synthesis of non-carbohydrate natural products. Stereoselective synthesis of aspicilin C-3—C-9 fragment

The C-3—C-9 main fragment of aspicilin was prepared via a fructose 1,6-diphosphate aldolase reaction. The same fragment was also synthesized by chemical transformation starting from D-arabinose. Key words: aldolase, aspicilin, arabinose, synthesis.