A molecular docking study of potential inhibitors and repurposed drugs against SARS-CoV-2 main protease enzyme

COVID-19 has affected millions of people. Although many drugs are in use to combat disease, there is not any sufficient treatment yet. Having critical role in propagation of the novel coronavirus (SARS-CoV-2) works Main Protease up into a significant drug target. We have performed a molecular docking study to define possible inhibitor candidates against SARS-CoV-2 Main Protease enzyme. Besides docking Remdesivir, Ribavirin, Chloroquine and 28 other antiviral inhibitors (totally 31 inhibitors) to Main Protease enzyme, we have also performed a molecular docking study of 2177 ligands, which are used against Main Protease for the first time by using molecular docking program Autodock4. All ligands were successfully docked into Main Protease enzyme binding site. Among all ligands, EY16 coded ligand which previously used as EBNA1-DNA binding blocker candidate showed the best score for Main Protease with a binding free energy of −10.83 ​kcal/mol which was also lower than re-docking score of N3 ligand (−10.72 ​kcal/mol) contained in crystal structure of Main Protease. After analyzing the docking modes and docking scores we have found that our ligands have better binding free energy values than the inhibitors in use of treatment. We believe that further studies such as molecular dynamics or Molecular Mechanic Poisson Boltzmann Surface Area studies can make contribution that is more exhaustive to the docking results.     

Impact of Magnesium(II) on Beryllium Fluorides in Solutions Studied by 19F NMR Spectroscopy

Beryllium fluorides are widely used in protein phosphorylation studies to get stable transition state analogs or near attack conformers, which has attracted much attention. BeF₃^? is one of the optimal phosphoryl (PO₃^?) analogs for its identical geometry and charge, and Mg²⁺ naturally participates in the phosphoryl binding in biological systems. In solutions, BeF₃^? coexists with other beryllium fluorides (BeF₄^2?, BeF₂ and BeF⁺) and magnesium fluorides, and there are equilibriums between these species. In this article, ¹⁹F NMR spectroscopy was applied to the investigation of the impact of magnesium(II) on beryllium fluorides. It has been found that when Mg²⁺ was introduced into the solutions, the chemical shifts, the intensities and the line widths of ¹⁹F signals of various beryllium fluoride complexes were changed. After ionic strength correction, these effects were remarkable only for BeF₄^2? and BeF₃^?, especially BeF₄^2?, when the concentration of the fluoride ion is relatively low. Mechanism of the effects is proposed which involves ion pair formation between Mg²⁺ and beryllium fluorides.     

Current Status of COVID-19 (Pre)Clinical Vaccine Development

The current COVID-19 pandemic has a tremendous impact on daily life world-wide. Despite the ability to dampen the spread of SARS-CoV-2, the causative agent of the diseases, through restrictive interventions, it is believed that only effective vaccines will provide sufficient control over the disease and revert societal live back to normal. At present, a double-digit number of efforts are devoted to the development of a vaccine against COVID-19. Here, we provide an overview of these (pre)clinical efforts and provide background information on the technologies behind these vaccines. In addition, we discuss potential hurdles that need to be addressed prior to mass scale clinical translation of successful vaccine candidates.     

Physicochemical properties of SARS-CoV-2 for drug targeting,virus inactivation and attenuation,vaccine formulation and quality control

The material properties of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its proteins are discussed. We review the viral structure, size, rigidity, lipophilicity, isoelectric point, buoyant density and centrifugation conditions, stability against pH, temperature, UV light, gamma radiation, and susceptibility to various chemical agents including solvents and detergents. Possible inactivation, downstream, and formulation conditions are given including suitable buffers and some first ideas for quality-control methods. This information supports vaccine development and discussion with competent authorities during vaccine approval and is certainly related to drug-targeting strategies and hygienics. Several instructive tables are given, including the pI and grand average of hydropathicity (GRAVY) of SARS-CoV-1 and -2 proteins in comparison. SARS-CoV-1 and SARS-CoV-2 are similar in many regards, so information can often be derived. Both are unusually stable, but sensitive at their lipophilic membranes. However, since seemingly small differences can have strong effects, for example, on immunologically relevant epitope settings, unevaluated knowledge transfer from SARS-CoV-1 to SARS-CoV-2 cannot be advised. Published knowledge regarding downstream processes, formulations and quality assuring methods is, as yet, limited. However, standard approaches employed for other viruses and vaccines seem to be feasible including virus inactivation, centrifugation conditions, and the use of adjuvants.     

An overview of emerging pollutants in air: Method of analysis and potential public health concern from human environmental exposure

Air pollutants are perhaps the largest cause of diseases and death in the world today. Increasing urbanization and industrialization have caused an increase in number of diverse forms and types of new pollutants, which are difficult to detect and characterize due to their stench behaviour and complex sources of production. Such pollutants have been called emerging pollutants (EPs) and their list is ever increasing. Therefore, the understanding of the method of analysis and health implication of (EPs) in air is critical to providing a more robust understanding of exposure routes, regulations and mitigation. EPs in air discussed in this study are not in any way exhaustive but limited to emerging VOCs (including acrylonitrile, 1−3-butadiene, chloroform, dichloromethane, ethylene oxides, formaldehyde, toluene, trichloroethylene, 1,4-Dioxane) and metals (arsenic, manganese, and vanadium), ultrafine particles, micro- and nano- plastics, engineered nanoparticles, diesel/black carbon and bioaerosols. Occurrence, detection and health implications of these EPs in air are still unfolding due to limited monitoring studies, lack of standard methodology and regulations. To address this knowledge gap, authors conducted an in-depth review of available information. Their spatial distribution, analytical methods and health implications are discussed including the novel coronavirus (COVID-19) as a potential EP in air. The study concluded with highlights of gaps in knowledge and suggestions to key areas for future research. This information is of general interest to environmental scientists and of specific interest to both health and sanitation workers and policymakers at private, government and international organizations.     

Nano-enabled biosensing systems for intelligent healthcare: towards COVID-19 management

Biosensors are emerging as efficient (sensitive and selective) and affordable analytical diagnostic tools for early-stage disease detection, as required for personalized health wellness management. Low-level detection of a targeted disease biomarker (pM level) has emerged extremely useful to evaluate the progression of disease under therapy. Such collected bioinformatics and its multi-aspects-oriented analytics is in demand to explore the effectiveness of a prescribed treatment, optimize therapy, and correlate biomarker level with disease pathogenesis. Owing to nanotechnology-enabled advancements in sensing unit fabrication, device integration, interfacing, packaging, and sensing performance at point-of-care (POC) has rendered diagnostics according to the requirements of disease management and patient disease profile i.e. in a personalized manner. Efforts are continuously being made to promote the state of art biosensing technology as a next-generation non-invasive disease diagnostics methodology. Keeping this in view, this progressive opinion article describes personalized health care management related analytical tools which can provide access to better health for everyone, with overreaching aim to manage healthy tomorrow timely. Considering accomplishments and predictions, such affordable intelligent diagnostics tools are urgently required to manage COVID-19 pandemic, a life-threatening respiratory infectious disease, where a rapid, selective and sensitive detection of human beta severe acute respiratory system coronavirus (SARS-COoV-2) protein is the key factor.     

Pandemic-Driven Development of a Medical-Grade,Economic and Decentralized Applicable Polyolefin Filament for Additive Fused Filament Fabrication

A polyolefin with certified biocompatibility according to USP class VI was used by our group as feedstock for filament-based 3D printing to meet the highest medical standards in order to print personal protective equipment for our university hospital during the ongoing pandemic. Besides the chemical resistance and durability, as well as the ability to withstand steam sterilization, this polypropylene (PP) copolymer is characterized by its high purity, as achieved by highly efficient and selective catalytic polymerization. As the PP copolymer is suited to be printed with all common printers in fused filament fabrication (FFF), it offers an eco-friendly cost–benefit ratio, even for large-scale production. In addition, a digital workflow was established focusing on common desktop FFF printers in the medical sector. It comprises the simulation-based optimization of personalized print objects, considering the inherent material properties such as warping tendency, through to validation of the process chain by 3D scanning, sterilization, and biocompatibility analysis of the printed part. This combination of digital data processing and 3D printing with a sustainable and medically certified material showed great promise in establishing decentralized additive manufacturing in everyday hospital life to meet peaks in demand, supply bottlenecks, and enhanced personalized patient treatment.     

Carnosine to Combat Novel Coronavirus (nCoV): Molecular Docking and Modeling to Cocrystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein

Aims: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. The current paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 cocrystallized with nCoV spike protein. Methods: First, the starting point was ACE2 inhibitors and their structure–activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. Parallel, at all stages, the authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 with nCoV spike protein. Results: Carnosine emerged as the best-known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the protein–protein structure, carnosine bound with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Conclusion: Carnosine has promising inhibitory interactions with host ACE2 and nCoV spike protein and hence could offer a potential mitigating effect against the current COVID-19 pandemic.