Search

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of 2533 diverse fragments resulted in 214 unique macrodomain-binders. An additional 60 molecules were selected from docking more than 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several fragment hits were confirmed by solution binding using three biophysical techniques (differential scanning fluorimetry, homogeneous time-resolved fluorescence, and isothermal titration calorimetry). The 234 fragment structures explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

ABSTRACT The SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. Crystallographic screening of diverse fragment libraries resulted in 214 unique macrodomain-binding fragments, out of 2,683 screened. An additional 60 molecules were selected from docking over 20 million fragments, of which 20 were crystallographically confirmed. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Several crystallographic and docking fragment hits were validated for solution binding using three biophysical techniques (DSF, HTRF, ITC). Overall, the 234 fragment structures presented explore a wide range of chemotypes and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors.

Abstract Background Hundreds of millions of people are infected with cryptosporidiosis annually, with immunocompromised individuals suffering debilitating symptoms and children in socioeconomically challenged regions at risk of repeated infections. There is currently no effective drug available. In order to facilitate the pursuit of anti-cryptosporidiosis targets and compounds, our study spans the classification of the Cryptosporidium parvum kinome and the structural and biochemical characterization of representatives from the CDPK family and a MAP kinase. Results The C. parvum kinome comprises over 70 members, some of which may be promising drug targets. These C. parvum protein kinases include members in the AGC, Atypical, CaMK, CK1, CMGC, and TKL groups; however, almost 35% could only be classified as OPK (other protein kinases). In addition, about 25% of the kinases identified did not have any known orthologues outside of Cryptosporidium spp. Comparison of specific kinases with their Plasmodium falciparum and Toxoplasma gondii orthologues revealed some distinct characteristics within the C. parvum kinome, including potential targets and opportunities for drug design. Structural and biochemical analysis of 4 representatives of the CaMK group and a MAP kinase confirms features that may be exploited in inhibitor design. Indeed, screening CpCDPK1 against a library of kinase inhibitors yielded a set of the pyrazolopyrimidine derivatives (PP1-derivatives) with IC50 values of < 10 nM. The binding of a PP1-derivative is further described by an inhibitor-bound crystal structure of CpCDPK1. In addition, structural analysis of CpCDPK4 identified an unprecedented Zn-finger within the CDPK kinase domain that may have implications for its regulation. Conclusions Identification and comparison of the C. parvum protein kinases against other parasitic kinases shows how orthologue- and family-based research can be used to facilitate characterization of promising drug targets and the search for new drugs.

Mining enterprises are energy intensive facilities. The capacity of single technological units can reach 5 MW. Variable-frequency drive systems are often used to set them in motion. The paper analyzes the features of choosing and using variable-frequency drives under diamond mining conditions. The study objective is to formulate and formalize the problems of introducing and operating variable-frequency drives at diamond-mining enterprises to further develop and implement guidelines for improving the performance of this drive type. To achieve this objective, the use of variable frequency drives in various process units of diamond mining should be studied and analyzed. The units are considered, for which in recent years, electric drive systems have been groundlessly (according to the authors) chosen by the engineering staff of enterprises. A technical and economic comparison of low-voltage frequency converters with the same power but different control modes is performed. The economic indicators of introducing high-voltage and low-voltage frequency converters into an existing electric drive system are calculated and represented as a comparative table. Conclusions are made on the need to proceed with the research and develop guidelines for implementing frequency converters at diamond-mining enterprises.

The article presents indicators of the hydropower potential of Kyrgyzstan, shows the share of small hydropower plants in the production of electric energy in the energy sector of the republic, reveals the problematic issues that need to be revealed in this work. A brief description of the existing automatic voltage regulation system and automatic field blanking system is given. Based on the analysis of existing systems, their shortcomings were identified and the main functions formulated for automatic voltage regulation systems in both static and dynamic modes associated with starting and stopping the generator, loading and dumping, as well as protective measures taken to ensure reliability operation of the hydraulic unit. The result of the research is the development of the main functional blocks in the system of automatic voltage regulation with a thyristor pathogen and a brief explanation of their work. The synthesis technique of the excitation current regulator of a synchronous generator and the main indicators obtained in the modernization process are shown. In conclusion, all the functions inherent in the modernized system for automatically controlling the excitation of a synchronous generator, aimed at the safe operation of the hydraulic unit, are noted.

The paper analyses the global demand for various energy resources in recent years. Nowadays, qualitative and quantitative changes in structure of distribution and consumption of energy resources take place. The paper has reviewed a number of papers predicting two-fold increase in the global energy production market by 2040. A number of other papers also predict the shift of energy demand from the USA and EU countries to the Asian market. The paper presents percentage distribution of world’s energy requirements satisfied by the six types of resources among which oil, gas, and coil are still predominant. Some papers have stated that the demand for natural gas will continue to grow faster than the demand for oil or coil in the future. To confirm or deny this theory the authors have designed the mathematical model showing trends in demand for gas compared to the total demand for oil and coal; as a result, two different polynomial functions have been obtained with almost the same probability confirming this prediction. Trends in energy production and change of global energy demand across regions over the past twenty years have been studied. The studies show that, in general, energy production has been increased for the last decade. However, due to economic crises fluctuations, energy production in EU countries has abruptly decreased; it results in displacement of the EU countries from the market by the countries of the Middle East and the Near East. The paper also notes such important factors as decrease in solid fuel production in Great Britain; steady increasing importance of renewable energy sources for the last few years; reducing of the rate of nuclear energy development by some key countries; general lack of energy recourses in EU countries, etc.

The present study is aimed to identify influence of Lakhta-Center visibility by means of photofixation results' analysis and their comparison with the results of the landscape and visual analysis performed by the Saint Petersburg Regional Committee of the International Council on Monuments and Sights (ICOMOS), report on research of Lakhta-Center high-rise dominant visibility influence on Saint Petersburg protected panoramas (2012), and assessment analysis of requested deviations' influence on formation of compositional and environmental characteristics of the urban environment based on a 3D reference model of the Saint Petersburg territory (2011). The study is supported by actual photos of cityscapes, thus, allowing assessing the situation reasonably and rationally. The performed work resulted in graphic materials, including photos and maps with reviews and classification of Lakhta-Center visibility upon perception of the main city panoramas from the tourist route combining the most popular sights of the city.

The article discusses the possibility of using data from smart electricity meters (SEM) to increase the accuracy of calculation losses in 0.4 kV low-voltage networks. An increase in accuracy can be achieved using actual data about the load graph of electricity consumers (in this case, 6(10)-0.4 kV transformer substations are meant). To date, the operating load factor is taken equal to 0.5, which does not always correspond to the actual data. Using SEM, actual load graphs can be obtained, which enable more accurate determination of the operating load factor. Consequently, the accuracy of calculation of electrical energy losses will be increased.