Inhibition of the predicted allosteric site of the SARS-CoV-2 main protease through flavonoids.

Since its emergence in 2019, coronavirus infection (COVID-19) has become a global pandemic and killed several million people worldwide. Even though several types of vaccines are available against the COVID-19 virus, SARS-CoV-2, new strains are emerging that pose a constant danger to vaccine effectiveness. In this computational study, we identified and predicted potent allosteric inhibitors of the SARS-CoV-2 main protease (Mpro). Via molecular docking and simulations, more than 100 distinct flavonoids were docked with the allosteric site of Mpro. Docking experiments revealed four top hit compounds (Hesperidin, Schaftoside, Brickellin, and Marein) that bound strongly to the Mpro predicted allosteric site. Simulation analyses further revealed that these continually interacted with the enzyme's allosteric region throughout the simulation time. ADMET and Lipinski drug likenesses were calculated to indicate the therapeutic value of the top four hits: They were non-toxic and exhibited high human intestinal absorption concentrations. These novel allosteric site inhibitors provide a higher chance of drugging SARS-CoV2 Mpro due to the rapid mutation rate of the viral enzyme's active sites. Our findings provide a new avenue for developing novel allosteric inhibitors of SARS-CoV-2 Mpro.Communicated by Ramaswamy H. Sarma.

Identification and Inhibition of the Druggable Allosteric Site of SARS-CoV-2 NSP10/NSP16 Methyltransferase through Computational Approaches.

Since its emergence in early 2019, the respiratory infectious virus, SARS-CoV-2, has ravaged the health of millions of people globally and has affected almost every sphere of life. Many efforts are being made to combat the COVID-19 pandemic's emerging and recurrent waves caused by its evolving and more infectious variants. As a result, novel and unexpected targets for SARS-CoV-2 have been considered for drug discovery. 2'-O-Methyltransferase (nsp10/nsp16) is a significant and appealing target in the SARS-CoV-2 life cycle because it protects viral RNA from the host degradative enzymes via a cap formation process. In this work, we propose prospective allosteric inhibitors that target the allosteric site, SARS-CoV-2 MTase. Four drug libraries containing ~119,483 compounds were screened against the allosteric site of SARS-CoV-2 MTase identified in our research. The identified best compounds exhibited robust molecular interactions and alloscore-score rankings with the allosteric site of SARS-CoV-2 MTase. Moreover, to further assess the dynamic stability of these compounds (CHEMBL2229121, ZINC000009464451, SPECS AK-91811684151, NCI-ID = 715319), a 100 ns molecular dynamics simulation, along with its holo-form, was performed to provide insights on the dynamic nature of these allosteric inhibitors at the allosteric site of the SARS-CoV-2 MTase. Additionally, investigations of MM-GBSA binding free energies revealed a good perspective for these allosteric inhibitor-enzyme complexes, indicating their robust antagonistic action on SARS-CoV-2 (nsp10/nsp16) methyltransferase. We conclude that these allosteric repressive agents should be further evaluated through investigational assessments in order to combat the proliferation of SARS-CoV-2.

Computational Study of SARS-CoV-2 RNA Dependent RNA Polymerase Allosteric Site Inhibition.

The COVID-19 pandemic has caused millions of fatalities since 2019. Despite the availability of vaccines for this disease, new strains are causing rapid ailment and are a continuous threat to vaccine efficacy. Here, molecular docking and simulations identify strong inhibitors of the allosteric site of the SARS-CoV-2 virus RNA dependent RNA polymerase (RdRp). More than one hundred different flavonoids were docked with the SARS-CoV-2 RdRp allosteric site through computational screening. The three top hits were Naringoside, Myricetin and Aureusidin 4,6-diglucoside. Simulation analyses confirmed that they are in constant contact during the simulation time course and have strong association with the enzyme's allosteric site. Absorption, distribution, metabolism, excretion and toxicity (ADMET) data provided medicinal information of these top three hits. They had good human intestinal absorption (HIA) concentrations and were non-toxic. Due to high mutation rates in the active sites of the viral enzyme, these new allosteric site inhibitors offer opportunities to drug SARS-CoV-2 RdRp. These results provide new information for the design of novel allosteric inhibitors against SARS-CoV-2 RdRp.

Antiviral activities of flavonoids.

Flavonoids are natural phytochemicals known for their antiviral activity. The flavonoids acts at different stages of viral infection, such as viral entrance, replication and translation of proteins. Viruses cause various diseases such as SARS, Hepatitis, AIDS, Flu, Herpes, etc. These, and many more viral diseases, are prevalent in the world, and some (i.e. SARS-CoV-2) are causing global chaos. Despite much struggle, effective treatments for these viral diseases are not available. The flavonoid class of phytochemicals has a vast number of medicinally active compounds, many of which are studied for their potential antiviral activity against different DNA and RNA viruses. Here, we reviewed many flavonoids that showed antiviral activities in different testing environments such as in vitro, in vivo (mice model) and in silico. Some flavonoids had stronger inhibitory activities, showed no toxicity & the cell proliferation at the tested doses are not affected. Some of the flavonoids used in the in vivo studies also protected the tested mice prophylactically from lethal doses of virus, and effectively prevented viral infection. The glycosides of some of the flavonoids increased the solubility of some flavonoids, and therefore showed increased antiviral activity as compared to the non-glycoside form of that flavonoid. These phytochemicals are active against different disease-causing viruses, and inhibited the viruses by targeting the viral infections at multiple stages. Some of the flavonoids showed more potent antiviral activity than the market available drugs used to treat viral infections.

Knowledge, attitudes, and practices (KAP) towards COVID-19 among university students in Pakistan: a cross-sectional study.

OBJECTIVES: Pakistan has taken unprecedented measures to control the spread of COVID-19. Complete lockdown followed by smart lockdown and quarantine centres was established. Their awareness and attitude towards COVID-19 had an impact on the individual behaviour of the precautionary measures. The current study examined the knowledge, attitudes and practices of university students in Pakistan. METHODS: An online cross-sectional study was conducted among university students in Pakistan. A questionnaire containing demographic and KAP information related to COVID-19 has been created. RESULTS: A total of 358 students responded to the survey, and 353 participants completed the study. Among the respondents, 61.5% were male, 76.8% were single, and 58.4% enrolled in a bachelor's degree. The results showed that most of the respondents (68%) had good knowledge about COVID-19, while the overall knowledge score was 8.78 ± 1.63 (range 1-10). The majority of the respondents (90.9%) were aware of COVID-19, 95.8% knew the sign and symptoms, and 83% of them knew about its transmission. We found a significant difference in knowledge scores across education and area of study p<0.05. More than half (53.5%) of the respondents were satisfied with the facilities provided by the government of Pakistan. The average practices score among the students was 5.08 ± 1.312. A significant difference was found among practice score and area of study p<0.05. CONCLUSIONS: Most of the students have an adequate level of knowledge and are doing better preventive measures against COVID-19. Health education initiatives are required to ensure best practice among the high-risk groups.

Hybrid-Quantum approach for the optimal lockdown to stop the SARS-CoV-2 community spread subject to maximizing nation economy globally (preprint)

Owing to the SARS-CoV-2 epidemic (severe acute respiratory coronavirus 2 syndromes), the global situation has changed drastically. Several countries, including India, Europe, U.S.A., introduced a full state/nation lockdown to minimize the disease transmission through human interaction after the virus entered the population and to minimize the loss of human life. Millions of people have gone unemployed due to lockdown implementation, resulting in business and industry closure and leading to a national economic slowdown. Therefore, preventing the spread of the COVID-19 virus in the world while also preserving the global economy is an essential problem requiring an effective and immediate solution. Using the compartmental epidemiology S, E, I, R or D (Susceptible, Exposed, Infectious, Recovery or Death) model extended to multiple population regions we predict the evolution of the SARS-CoV-2 disease and construct an optimally scheduled lockdown calendar to execute lockdown over phases, using the well-known Knapsack problem. A comparative analysis of both classical and quantum models shows that our model decreases SARS-CoV-2 active cases while retaining the average global economic factor, GDP, in contrast to the scenario with no lockdown.

Innate immune-mediated antiviral response to SARS-CoV-2 and convalescent sera a potential prophylactic and therapeutic agent to tackle COVID-19.

The whole world is confronting the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Unfortunately, there is no vaccine to prevent novel coronavirus infection. Besides several experimental drugs, the strong immune responses and convalescent sera are the current two potential options to tackle coronavirus disease 2019 (COVID-19) infection. Innate immune-mediated antiviral responses are initiated by the recognition of viral invasion through pathogen-associated molecular patterns (PAMPs). In coronavirus, the PAMPs are recognized by Toll-like receptors 3 and 7, endosomal ribonucleic acid receptors, RNA in cytosol, and by pattern recognition receptor (RIG-1) in the alveolar cells and site of invasion. Nuclear factor-κB and interferon regulatory transcription factor (IRF3) are activated in response to the above recognition episode and translocate to nucleus. These transcription factors in the nucleus initiate the expression of interferon type 1 and pro-inflammatory cytokine storm, which leads to first line of defense at the site of viral entrance. The effectiveness of innate immune system is greatly relies on type 1 interferons and its cascade, because of their role in the inhibition of viral replication and initiation of adaptive immune responses. The successful interferon type 1 response put down the viral replication and transmission at prompt point. Passive immunization is the administering of antibodies into infected patients, which is taken from recovered individuals. The convalescent sera of the recovered COVID-19 patients are containing antiviral neutralizing antibodies and are used therapeutically for infected individuals by SARS-CoV-2 and for the purpose of prophylaxis in exposed individuals. The convalescent sera is found effective when administered early at the onset of symptoms.

COVID-19: Review of Epidemiology and Potential Treatments Against 2019 Novel Coronavirus.

An epidemic of extreme respiratory deterrence, pneumonia and shortness of breath, the SARS-CoV-2 viral infection began in Wuhan, Hubei Province, China in December 2019, and rapidly spread across China and beyond, with human to human transmission. On February 12, 2020, World Health Organization officially named the new coronavirus disease as coronavirus disease 19 (COVID-19). Most COVID-19 patients were diagnosed with pneumonia and many were treated using Chinese medicines and other secondary therapies. As of April 22, 2020, the total figure of infected patients has crossed 2.6 million people worldwide with over 180,000 deaths and 700,000 patients that have recovered. Preliminary reports suggest that certain drugs, such as chloroquine and antiviral nucleotide analogues such as remdesivir, which inhibit viral replication, can target the new coronavirus, although their usefulness in the clinic is still under debate. An expert US committee developed the US NIH guidelines for COVID-19 treatment, which was just released and will be regularly updated. This manuscript reviews the epidemiology, etiology, mortality, COVID-19 clinical symptoms, and potential therapeutic drugs, while highlighting the seriousness and damage-induced by SARS-CoV-2.