Analysis of meteorology-chemistry interactions during air pollution episodes using online coupled models within AQMEII Phase-2

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).This study reviews the top ranked meteorology and chemistry interactions in online coupled models recommended by an experts’ survey conducted in COST Action EuMetChem and examines the sensitivity of those interactions during two pollution episodes: the Russian forest fires 25 Jul -15 Aug 2010 and a Saharan dust transport event from 1 Oct -31 Oct 2010 as a part of the AQMEII phase-2 exercise. Three WRF-Chem model simulations were performed for the forest fire case for a baseline without any aerosol feedback on meteorology, a simulation with aerosol direct effects only and a simulation including both direct and indirect effects. For the dust case study, eight WRF-Chem and one WRF-CMAQ simulations were selected from the set of simulations conducted in the framework of AQMEII. Of these two simulations considered no feedbacks, two included direct effects only and five simulations included both direct and indirect effects. The results from both episodes demonstrate that it is important to include the meteorology and chemistry interactions in online-coupled models. Model evaluations using routine observations collected in AQMEII phase-2 and observations from a station in Moscow show that for the fire case the simulation including only aerosol direct effects has better performance than the simulations with no aerosol feedbacks or including both direct and indirect effects. The normalized mean biases are significantly reduced by 10-20% for PM10 when including aerosol direct effects. The analysis for the dust case confirms that models perform better when including aerosol direct effects, but worse when including both aerosol direct and indirect effects, which suggests that the representation of aerosol indirect effects needs to be improved in the model.Peer reviewedFinal Published versio

Quantum mechanical studies of lincosamides

Lincosamides are a class of antibiotics used both in clinical and veterinary practice for a wide range of pathogens. This group of drugs inhibits the activity of the bacterial ribosome by binding to the 23S RNA of the large ribosomal subunit and blocking protein synthesis. Currently, three X-ray structures of the ribosome in complex with clindamycin are available in the Protein Data Bank, which reveal that there are two distinct conformations of the pyrrolidinyl propyl group of the bound clindamycin. In this work, we used quantum mechanical methods to investigate the probable conformations of clindamycin in order to explain the two binding modes in the ribosomal 23S RNA. We studied three lincosamide antibiotics: clindamycin, lincomycin, and pirlimycin at the B3LYP level with the 6-31G** basis set. The focus of our work was to connect the conformational landscape and electron densities of the two clindamycin conformers found experimentally with their physicochemical properties. For both functional conformers, we applied natural bond orbital (NBO) analysis and the atoms in molecules (AIM) theory, and calculated the NMR parameters. Based on the results obtained, we were able to show that the structure with the intramolecular hydrogen bond C=O…H–O is the most stable conformer of clindamycin. The charge transfer between the pyrrolidine-derivative ring and the six-atom sugar (methylthiolincosamide), which are linked via an amide bond, was found to be the dominant factor influencing the high stability of this conformer

Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors

Azithromycin-chloroquine and the intermittent preventive treatment of malaria in pregnancy

In the high malaria-transmission settings of sub-Saharan Africa, malaria in pregnancy is an important cause of maternal, perinatal and neonatal morbidity. Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) reduces the incidence of low birth-weight, pre-term delivery, intrauterine growth-retardation and maternal anaemia. However, the public health benefits of IPTp are declining due to SP resistance. The combination of azithromycin and chloroquine is a potential alternative to SP for IPTp. This review summarizes key in vitro and in vivo evidence of azithromycin and chloroquine activity against Plasmodium falciparum and Plasmodium vivax, as well as the anticipated secondary benefits that may result from their combined use in IPTp, including the cure and prevention of many sexually transmitted diseases. Drug costs and the necessity for external financing are discussed along with a range of issues related to drug resistance and surveillance. Several scientific and programmatic questions of interest to policymakers and programme managers are also presented that would need to be addressed before azithromycin-chloroquine could be adopted for use in IPTp

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