scholarly journals X-ray Structure-Based Chemoinformatic Analysis Identifies Promiscuous Ligands Binding to Proteins from Different Classes with Varying Shapes

2020 ◽  
Vol 21 (11) ◽  
pp. 3782 ◽  
Author(s):  
Christian Feldmann ◽  
Jürgen Bajorath
Keyword(s):  
Large Scale ◽  
Wide Spectrum ◽  
Basic Research ◽  
Molecular Properties ◽  
Binding Modes ◽  
Target Structure ◽  
Computational Investigation ◽  
Activity Data ◽  
X Ray ◽  
Protein Classes

(1) Background: Compounds with multitarget activity are of interest in basic research to explore molecular foundations of promiscuous binding and in drug discovery as agents eliciting polypharmacological effects. Our study has aimed to systematically identify compounds that form complexes with proteins from distinct classes and compare their bioactive conformations and molecular properties. (2) Methods: A large-scale computational investigation was carried out that combined the analysis of complex X-ray structures, ligand binding modes, compound activity data, and various molecular properties. (3) Results: A total of 515 ligands with multitarget activity were identified that included 70 organic compounds binding to proteins from different classes. These multiclass ligands (MCLs) were often flexible and surprisingly hydrophilic. Moreover, they displayed a wide spectrum of binding modes. In different target structure environments, binding shapes of MCLs were often similar, but also distinct. (4) Conclusions: Combined structural and activity data analysis identified compounds with activity against proteins with distinct structures and functions. MCLs were found to have greatly varying shape similarity when binding to different protein classes. Hence, there were no apparent canonical binding shapes indicating multitarget activity. Rather, conformational versatility characterized MCL binding.

scholarly journals Biological Activity Profiles of Multitarget Ligands from X-ray Structures

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 794
Author(s):  
Christian Feldmann ◽  
Jürgen Bajorath
Keyword(s):  
Large Scale ◽  
Pharmaceutical Research ◽  
Data Consistency ◽  
Exploratory Research ◽  
Activity Data ◽  
X Ray ◽  
X Ray Crystallography ◽  
Large Scale Analysis ◽  
Compound Promiscuity ◽  
Different Sources

In pharmaceutical research, compounds with multitarget activity receive increasing attention. Such promiscuous chemical entities are prime candidates for polypharmacology, but also prone to causing undesired side effects. In addition, understanding the molecular basis and magnitude of multitarget activity is a stimulating topic for exploratory research. Computationally, compound promiscuity can be estimated through large-scale analysis of activity data. To these ends, it is critically important to take data confidence criteria and data consistency across different sources into consideration. Especially the consistency aspect has thus far only been little investigated. Therefore, we have systematically determined activity annotations and profiles of known multitarget ligands (MTLs) on the basis of activity data from different sources. All MTLs used were confirmed by X-ray crystallography of complexes with multiple targets. One of the key questions underlying our analysis has been how MTLs act in biological screens. The results of our analysis revealed significant variations of MTL activity profiles originating from different data sources. Such variations must be carefully considered in promiscuity analysis. Our study raises awareness of these issues and provides guidance for large-scale activity data analysis.

Model and Method for Contributor’s Quality Assessment in Community Image Tagging Systems

2018 ◽  
pp. 45-51
Author(s):  
A. V. Ponomarev
Keyword(s):  
Large Scale ◽  
Wide Spectrum ◽  
Preference Relation ◽  
Pairwise Comparison ◽  
Ground Truth ◽  
Comparison Method ◽  
Characteristic Matrix ◽  
Image Tagging ◽  
Proposed Model

Introduction: Large-scale human-computer systems involving people of various skills and motivation into the information processing process are currently used in a wide spectrum of applications. An acute problem in such systems is assessing the expected quality of each contributor; for example, in order to penalize incompetent or inaccurate ones and to promote diligent ones.Purpose: To develop a method of assessing the expected contributor’s quality in community tagging systems. This method should only use generally unreliable and incomplete information provided by contributors (with ground truth tags unknown).Results:A mathematical model is proposed for community image tagging (including the model of a contributor), along with a method of assessing the expected contributor’s quality. The method is based on comparing tag sets provided by different contributors for the same images, being a modification of pairwise comparison method with preference relation replaced by a special domination characteristic. Expected contributors’ quality is evaluated as a positive eigenvector of a pairwise domination characteristic matrix. Community tagging simulation has confirmed that the proposed method allows you to adequately estimate the expected quality of community tagging system contributors (provided that the contributors' behavior fits the proposed model).Practical relevance: The obtained results can be used in the development of systems based on coordinated efforts of community (primarily, community tagging systems). 

scholarly journals The Influence of Varying Fluorination Patterns on the Thermodynamics and Kinetics of Benzenesulfonamide Binding to Human Carbonic Anhydrase II

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 509 ◽  
Author(s):  
Steffen Glöckner ◽  
Khang Ngo ◽  
Björn Wagner ◽  
Andreas Heine ◽  
Gerhard Klebe
Keyword(s):  
Carbonic Anhydrase ◽  
Carbonic Anhydrase Ii ◽  
The Novel ◽  
Binding Modes ◽  
X Ray ◽  
Structure Activity ◽  
Small Set ◽  
Novel Method ◽  
Human Carbonic Anhydrase ◽  
Kinetics Of

The fluorination of lead-like compounds is a common tool in medicinal chemistry to alter molecular properties in various ways and with different goals. We herein present a detailed study of the binding of fluorinated benzenesulfonamides to human Carbonic Anhydrase II by complementing macromolecular X-ray crystallographic observations with thermodynamic and kinetic data collected with the novel method of kinITC. Our findings comprise so far unknown alternative binding modes in the crystalline state for some of the investigated compounds as well as complex thermodynamic and kinetic structure-activity relationships. They suggest that fluorination of the benzenesulfonamide core is especially advantageous in one position with respect to the kinetic signatures of binding and that a higher degree of fluorination does not necessarily provide for a higher affinity or more favorable kinetic binding profiles. Lastly, we propose a relationship between the kinetics of binding and ligand acidity based on a small set of compounds with similar substitution patterns.

scholarly journals On the relation between mini-halos and AGN feedback in clusters of galaxies

2020 ◽  
Vol 499 (2) ◽  
pp. 2934-2958
Author(s):  
A Richard-Laferrière ◽  
J Hlavacek-Larrondo ◽  
R S Nemmen ◽  
C L Rhea ◽  
G B Taylor ◽  
...  
Keyword(s):  
Large Scale ◽  
State Of The Art ◽  
Vital Role ◽  
Clusters Of Galaxies ◽  
Relativistic Jets ◽  
X Ray ◽  
Core Cluster ◽  
Central Galaxy ◽  
Central Regions ◽  
Radio Power

ABSTRACT A variety of large-scale diffuse radio structures have been identified in many clusters with the advent of new state-of-the-art facilities in radio astronomy. Among these diffuse radio structures, radio mini-halos are found in the central regions of cool core clusters. Their origin is still unknown and they are challenging to discover; less than 30 have been published to date. Based on new VLA observations, we confirmed the mini-halo in the massive strong cool core cluster PKS 0745−191 (z = 0.1028) and discovered one in the massive cool core cluster MACS J1447.4+0827 (z = 0.3755). Furthermore, using a detailed analysis of all known mini-halos, we explore the relation between mini-halos and active galactic nucleus (AGN) feedback processes from the central galaxy. We find evidence of strong, previously unknown correlations between mini-halo radio power and X-ray cavity power, and between mini-halo and the central galaxy radio power related to the relativistic jets when spectrally decomposing the AGN radio emission into a component for past outbursts and one for ongoing accretion. Overall, our study indicates that mini-halos are directly connected to the central AGN in clusters, following previous suppositions. We hypothesize that AGN feedback may be one of the dominant mechanisms giving rise to mini-halos by injecting energy into the intra-cluster medium and reaccelerating an old population of particles, while sloshing motion may drive the overall shape of mini-halos inside cold fronts. AGN feedback may therefore not only play a vital role in offsetting cooling in cool core clusters, but may also play a fundamental role in re-energizing non-thermal particles in clusters.

scholarly journals X-Ray Emission Differences in SNR MSH14-63

1998 ◽  
Vol 11 (1) ◽  
pp. 393-393
Author(s):  
Fangjun Lu ◽  
Mei Wu ◽  
Tipei Li ◽  
Xuejun Sun
Keyword(s):  
Large Scale ◽  
Physical Characteristics ◽  
Energy Bands ◽  
X Ray

In the paper we report the discovery of X-ray emission differences in SNR MSH14-63 based on the ROSAT PSPC observation. The structures of MSH14-63 are different in different energy bands. These images along with the radial brightness distributions in these energy bands show the existence of a region which only emit X-ray photons harder than l.OkeV. Though weak, there actually exist large scale X-ray emissions beyond the bright rim in many parts of the northeast remnant component, which is in conflict with the Sedov phase assumption used in previous research. These new soft X-ray features provide astronomers more information to study its physical characteristics.

scholarly journals The Hot Universe with XRISM and Athena

2018 ◽  
Vol 14 (S342) ◽  
pp. 29-36
Author(s):  
M. Guainazzi ◽  
M. S. Tashiro
Keyword(s):  
Electromagnetic Radiation ◽  
Large Scale ◽  
Cosmological Evolution ◽  
X Ray ◽  
Hot Gas ◽  
Cosmic Vision ◽  
Esa Cosmic Vision ◽  
The Universe

AbstractX-ray spectroscopy is key to address the theme of “The Hot Universe”, the still poorly understood astrophysical processes driving the cosmological evolution of the baryonic hot gas traceable through its electromagnetic radiation. Two future X-ray observatories: the JAXA-led XRISM (due to launch in the early 2020s), and the ESA Cosmic Vision L-class mission Athena (early 2030s) will provide breakthroughs in our understanding of how and when large-scale hot gas structures formed in the Universe, and in tracking their evolution from the formation epoch to the present day.

Multinational Enterprises and the Globalization of Medicine: Siemens and the Business of X-ray Equipment in Non-Western Markets, 1900–1939

2014 ◽  
Vol 15 (4) ◽  
pp. 820-848
Author(s):  
Pierre-Yves Donzé
Keyword(s):  
International Organizations ◽  
Multinational Enterprises ◽  
Large Scale ◽  
Multinational Enterprise ◽  
Central Africa ◽  
Great Difficulty ◽  
X Ray ◽  
Hospital Development ◽  
Slight Growth ◽  
The 19Th Century

Whereas the globalization of medicine since the middle of the 19th century has primarily been approached as the sociopolitical and cultural outcome of imperialism, this article argues that Western big business also played a major role through the worldwide export of standardized medical technologies. It focuses on the expansion of Siemens on the X-ray equipment market in non-Western countries during the first half of the twentieth century. This German multinational enterprise experienced slight growth from the mid-1920s onwards but relied mainly on two markets (Argentina and Brazil). It specialized in providing large-scale equipment to a few urban hospitals and engaged during the 1930s in large-scale hospital development together with local authorities and international organizations in various countries (China, Peru, and Central Africa). However, Siemens had great difficulty in expanding its business to include private doctors and inland outlets, where it faced intense competition from other Western X-ray producers. This paper emphasizes that this shortcoming stemmed from a direct application of the European strategy (high-quality, expensive equipment for hospitals) to non-Western markets, where health systems differed.

Soft-X-ray spectra of highly charged Au ions in an electron-beam ion trap

2001 ◽  
Vol 79 (2-3) ◽  
pp. 153-162 ◽  
Author(s):  
E Träbert ◽  
P Beiersdorfer ◽  
K B Fournier ◽  
S B Utter ◽  
K L Wong
Keyword(s):  
Electron Beam ◽  
Beam Energy ◽  
Large Scale ◽  
Ion Trap ◽  
Electron Beam Energy ◽  
X Ray ◽  
Maximum Charge ◽  
Electron Beam Ion Trap ◽  
Atomic Structure Calculations ◽  
Structure Calculations

Systematic variation of the electron-beam energy in an electron-beam ion trap has been employed to produce soft-X-ray spectra (20 to 60 Å) of Au with well-defined maximum charge states ranging from Br- to Co-like ions. Guided by large-scale relativistic atomic structure calculations, the strongest Δn = 0 (n = 4 to n' = 4) transitions in Rb- to Cu-like ions (Au42+ – Au50+) have been identified. PACS Nos.: 32.30Rj, 39.30+w, 31.50+w, 32.20R

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