X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M^(pro)), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M^(pro). In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2

Massive X-ray screening reveals two allosteric drug binding sites of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of repurposing drug libraries containing 5953 individual compounds against the SARS-CoV-2 main protease (Mpro), which is a potent drug target as it is essential for the virus replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. Interestingly, two compounds bind outside the active site to the native dimer interface in close proximity to the S1 binding pocket. Another compound binds in a cleft between the catalytic and dimerization domain of Mpro. Neither binding site is related to the enzymatic active site and both represent attractive targets for drug development against SARS-CoV-2. This X-ray screening approach thus has the potential to help deliver an approved drug on an accelerated time-scale for this and future pandemics

X ray screening identifies active site and allosteric inhibitors of SARS CoV 2 main protease

The coronavirus disease COVID 19 caused by SARS CoV 2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID 19, we have performed a high throughput x ray crystallographic screen of two repurposing drug libraries against the SARS CoV 2 main protease Mpro , which is essential for viral replication. In contrast to commonly applied x ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three dimensional protein structures, we identified 37 compounds that bind to Mpro. In subsequent cell based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS CoV

Developing green supply chain management taxonomy-based decision support system

The aim of this paper is to develop a comprehensive taxonomy of green supply chain management (GSCM) practices and develop a structural equation modelling-driven decision support system following GSCM taxonomy for managers to provide better understanding of the complex relationship between the external and internal factors and GSCM operational practices. Typology and/or taxonomy play a key role in the development of social science theories. The current taxonomies focus on a single or limited component of the supply chain. Furthermore, they have not been tested using different sample compositions and contexts, yet replication is a prerequisite for developing robust concepts and theories. In this paper, we empirically replicate one such taxonomy extending the original study by (a) developing broad (containing the key components of supply chain) taxonomy; (b) broadening the sample by including a wider range of sectors and organisational size; and (c) broadening the geographic scope of the previous studies. Moreover, we include both objective measures and subjective attitudinal measurements. We use a robust two-stage cluster analysis to develop our GSCM taxonomy. The main finding validates the taxonomy previously proposed and identifies size, attitude and level of environmental risk and impact as key mediators between internal drivers, external drivers and GSCM operational practices

Estrutura da cadeia reversa: "caminhos" e "descaminhos" da embalagem PET Structure of the reverse chain: "ways" of PET packing

O trabalho propõe-se a discutir as possibilidades, limites e desafios da reciclagem de PET - Politereftalato de Etileno. Como fundamentação teórico-conceitual, recorre à discussão sobre a natureza e o alcance da logística reversa, analisando as estratégias para estruturação da cadeia de reciclagem. A pesquisa é de caráter exploratório, com adoção de diferentes estratégias para a coleta de dados, envolvendo fontes secundárias produzidas por órgãos públicos, instituições especializadas e mídia, e ainda entrevistas semi-estruturadas com especialistas na área. Os resultados apontam que múltiplos atores estão envolvidos na estrutura da cadeia reversa do PET e que, apesar do avanço no volume de reciclagem, nenhum dos setores, seja público ou privado, consegue individualmente organizar-se para o alcance da efetividade operacional e ambiental desejável no cenário brasileiro. O alcance de bons resultados depende, sobretudo, do investimento nos dois extremos da cadeia reversa: na coleta seletiva e no mercado para o produto reciclado.<br>The work discuss the possibilities, limits and challenges of the recycling of PET packing in the Brazilian case. The authors analyze the nature and the function of the reverse logistics and its strategies for articulation of the recycling chain. The research is based in the exploratory methodological approach, with adoption of different strategies for the collection of data, involving secondary sources produced by public institutions, specialized organizations and media, and still, interviews semi-structured with specialists in the area. The results point that the Brazilian public and private sectors doesn’t get to organize this activity in the desirable environmental scale. Good performances in the PET packing reverse chain depends on investing in the selective collection and in the market for the recycled products