Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification

One of the initial steps of modern drug discovery is the identification of small organic molecules able to inhibit a target macromolecule of therapeutic interest. A small proportion of these hits are further developed into lead compounds, which in turn may ultimately lead to a marketed drug. A commonly used screening protocol used for this task is high-throughput screening (HTS). However, the performance of HTS against antibacterial targets has generally been unsatisfactory, with high costs and low rates of hit identification. Here, we present a novel computational methodology that is able to identify a high proportion of structurally diverse inhibitors by searching unusually large molecular databases in a time-, cost- and resource-efficient manner. This virtual screening methodology was tested prospectively on two versions of an antibacterial target (type II dehydroquinase from Mycobacterium tuberculosis and Streptomyces coelicolor), for which HTS has not provided satisfactory results and consequently practically all known inhibitors are derivatives of the same core scaffold. Overall, our protocols identified 100 new inhibitors, with calculated K_i ranging from 4 to 250 μM (confirmed hit rates are 60% and 62% against each version of the target). Most importantly, over 50 new active molecular scaffolds were discovered that underscore the benefits that a wide application of prospectively validated in silico screening tools is likely to bring to antibacterial hit identification.     

On Floating‐Point Normal Vectors

In this paper we analyze normal vector representations. We derive the error of the most widely used representation, namely 3D floating‐point normal vectors. Based on this analysis, we show that, in theory, the discretization error inherent to single precision floating‐point normals can be achieved by 2^50.2 uniformly distributed normals, addressable by 51 bits. We review common sphere parameterizations and show that octahedron normal vectors perform best: they are fast and stable to compute, have a controllable error, and require only 1 bit more than the theoretical optimal discretization with the same error.     

Simulation of Fluid Flow and Oscillation of the Argon Oxygen Decarburization (AOD) Process

The oscillation of argon oxygen decarburization (AOD) converters is flow related and depends on the process parameters (e.g., vessel geometry, melt fill height, process gas type and blowing rate, vessel tilting angle, as well as geometry, number, and arrangement of the side-wall nozzles). For a 120-ton AOD converter with seven submerged side-wall nozzles, plant tests, physical simulations on a 1:4 scale water model, and computational fluid dynamics simulations have been done. The investigations show that the penetration depth of an inert gas jet into the melt does not exceed approximately 0.4 m. The plumes are located close to the nozzle-side converter wall and induce a large-scale primary vortex as well as intensive surface movements; both are responsible for the oscillation. Several process mechanisms were investigated. The oscillation is highest in the last stage of the dynamic blow and is still high during the reduction stage. As the amount of inert gas increases, the vibration level also increases. Inert gas has a greater influence on the oscillation than oxygen. Tilting the converter around 8 deg clearly leads to more intensive oscillations. Increasing the blowing rate increases the forces and torques acting on the vessel, whereas the oscillation frequency remains nearly constant. A varying fill level does not influence the vibration level the same way as the blowing rate. The operational test shows, for example, that the maximum torque does not depend on the heat size when the latter varies between –8 pct and +21 pct of the nominal heat size. The water model test shows decreasing forces and torques with a rising fill level.     

Mixed crystalline films of co-evaporated hydrogen- and fluorine-terminated phthalocyanines and their application in photovoltaic devices

Blends of organic electron and hole conductive materials are widely used for ambipolar charge carrier transport and photovoltaic cells. An obvious choice for donor–acceptor blends are organic semiconducting materials in their hydrogenated and fluorinated form, since they combine potentially suitable electronic properties with structural compatibility of the two constituents. This study focuses on the structural, optical, and electrical properties of blends using hydrogenated copper-phthalocyanine (H₁₆CuPc) in combination with its per-fluorinated version (F₁₆CuPc). Using X-ray scattering, scanning force microscopy and optical absorption measurements we show that mixed crystalline films are obtained by co-evaporation of the two materials. Electrical transport measurements reveal a profound reduction of the current for bipolar charge injection in mixed films. We discuss the formation of self-trapped charge transfer excitons as possible explanation for this unexpected behaviour, which impedes the usability of this system in photovoltaic cells.     

A refined search tree technique for Dominating Set on planar graphs

We establish a refined search tree technique for the parameterized DOMINATING SET problem on planar graphs. Here, we are given an undirected graph and we ask for a set of at most k vertices such that every other vertex has at least one neighbor in this set. We describe algorithms with running times O(8^kn) and O(8^kk+n³), where n is the number of vertices in the graph, based on bounded search trees. We describe a set of polynomial time data-reduction rules for a more general “annotated” problem on black/white graphs that asks for a set of k vertices (black or white) that dominate all the black vertices. An intricate argument based on the Euler formula then establishes an efficient branching strategy for reduced inputs to this problem. In addition, we give a family examples showing that the bound of the branching theorem is optimal with respect to our reduction rules. Our final search tree algorithm is easy to implement; its analysis, however, is involved.     

Fluorkunststoffe in der chemischen Verfahrenstechnik,insbesondere als Auskleidungs-/Beschichtungswerkstoffe

Fluoroplastics in chemical process engineering, especially as lining/coating materials Fluroplastich such as PTFE (Hostaflon®, Teflon®, etz.), PFA/TFA, FEP, PVDF, ECTFE, ETFE, PCTFE are largely known on the market and accepted in all industries for their excellent properties. Whereas in machine design and the automotive industry their low friction value and in the electrical industry their good dielectric values are essentially decisive, their universal chemical and high thermal resistance, their outstanding anti-adhesivity and phosiological inertness ensured their acceptance in the chemical and generically related industries. All of them are processed thermoplastically with only the PTFE having an exceptional position as it can only be processed by the sintering method and requires special techniques also for subsequent operations (e.g. shaping and welding). Their characteristics represent the basis for a lot of applications in the chemical and electroplating industry, the pharmaceutical and food industry, the laboratory and semi-conductor field as well as in environmental protection where fluoroplastics are used as finished parts such as seals, bearings, diaphragms, compensators, injection-moulded items, heating panels, heat exchangers, etc. Besides fluoroplastics semi-finished parts offer outstanding chances in chemical process engineering. For example steel tanks and sections as well as pipelines get corrosion-proof liners or evelopes against liquid or gaseous media. While the so-called heavy corrosion prevention is usually ensured with thicker material (3 to 4 mm), fluoroplastic coatings possibly offer a limited protection against chemicals only as their maximum coat thickness is approx. 1 mm. Therefore fluoroplastic coatings are mostly applied where it is a question of providing light corrosion prevention or anti-adhesivity and with parts of complex design which can neither be lined nor enveloped as e.g. agitors, spherical inserts, perforated plates, etc.     

Einfluß der Schrottvorwärmung mit Erdgas und Sauerstoff im Konverter auf den Sauerstoffumsatz des LD-Verfahrens

Stand der Erkenntnisse und Ziel der eigenen Versuche. Anlagenbeschreibung und Betriebsbeobachtungen. Untersuchung der Schlackenbildung während der Schrottvorwärmung. Änderungen der Roheisenzusammensetzung durch Reaktionen mit den Vorwärmschlacken. Betrachtungen zur Sauerstoffbilanz.