A sustainable approach for the degradation kinetics study and stability assay of the SARS-CoV-2 oral antiviral drug Molnupiravir.

Molnupiravir (MPV) is the first direct-acting oral antiviral drug that effectively decreases nasopharyngeal infections with SARS-CoV-2 virus. The stability of MPV was tested by subjecting the drug to various stress conditions. The drug is liable to oxidative, acidic, and alkaline degradation and showed significant stability against thermal degradation. Mass spectrometry identified the degradation products and guided suggestion of the degradation patterns. Interestingly, while inspecting the UV-absorption spectra, we observed no absorbance at 270 nm for the products of the three degradation pathways (c.f. intact MPV). Direct spectrophotometry seemed a solution that perfectly fit the purpose of the stability assay method in our case. It avoids sophisticated instrumentation and complex mathematical data manipulation. The method determined MPV accurately (100.32% ± 1.62) and selectively (99.49% ± 1.63) within the linear range of 1.50 × 10-5-4.0 × 10-4 M and down to a detection limit of 0.48 × 10-5 M. The proposed method is simple and does not require any preliminary separation or derivatization steps. The procedure proved its validity as per the ICH recommendations. The specificity was assessed in the presence of up to 90% degradation products. The study evaluated the greenness profile of the proposed analytical procedure using the National Environmental Methods Index (NEMI), the Analytical Eco-Scale, and the Green Analytical Procedure Index (GAPI). The three metrics unanimously agreed that the developed procedure results in a greener profile than the reported method. The method investigated the degradation reactions' kinetics and evaluated the reaction order, rate constant, and half-life time for each degradation process.

Acceptance and hesitancy to receive COVID-19 vaccine among university students in Egypt: a nationwide survey.

BACKGROUND: The public's willingness to be vaccinated will determine the success of the COVID-19 vaccination program. The aim of this study was to identify acceptance and hesitancy to receive COVID-19 vaccine among university students in Egypt, assess their level of knowledge about COVID-19 vaccine and identify factors that influence their intention towards COVID-19 vaccination. METHODS: A standardized and self-administered questionnaire was distributed among university students allover Egypt. The questionnaire included sociodemographic data, intention to receive COVID-19 vaccine, knowledge and beliefs about it and status of COVID-19 vaccination. Logistic regression analysis was used to determine factors associated with COVID-19 vaccine acceptancy. RESULTS: A total of 1071 of university students were involved, with a mean age of 20.51 years (SD = 1.66) and 68.2% were females. COVID-19 vaccination acceptability rate was 69.0% while hesitancy was 20.8% and resistancy was 10.2%. Median knowledge score of 4 out of 8 (IQR = 8). The main motivation for vaccine acceptance was fear of being infected (53.6%) and desire to get back to normal life (51.0%) while the main barriers against getting vaccinated were being afraid of serious side effects. Univariate regression analysis revealed an increasing likelihood of vaccine acceptancy associated with an active lifestyle (OR 1.35, 95% CI 1.04-1.75, p = 0.025), a high knowledge score (OR 1.53, 95% CI 1.42-1.66, p < 0.001), and positive vaccine beliefs. CONCLUSION: There is a high rate of acceptability of COVID-19 vaccination among university students. Vaccine acceptability is associated with an active lifestyle, a high knowledge score and positive vaccine beliefs. Educational campaigns and efforts aiming to raise awareness about safety and efficacy of COVID-19 vaccines need to be directed to this important population.

Correlation between oxygen saturation of patient and severity index of Covid 19 pneumonia on CT.

OBJECTIVE: To investigate the correlation between capillary blood oxygen saturation and computerised tomography severity index in patients with coronavirus disease-2019 pneumonia. METHODS: The cross-sectional analytical study was conducted at the coronavirus disease-2019 ward of Nishtar Medical University and Hospital, Multan, Pakistan, June 1, 2020, to June 1, 2021. At the time of admission, capillary oxygen saturation of all patients was measured. Pulmonary computerised tomography scans were then performed, and computerised tomography severity index was calculated. Data was analysed using SPSS 18. Results: Of the 170 patients, 90 (52.9%) were males and 80(47%) were females. The overall mean age of the sample was 56.32±12.45 years. At the time of admission, the mean oxygen saturation was 88.9±6.53% and the mean severity index was 15.01±7.79. Overall, 22(12.9%) patients had hypoxia and the severity index reading was significantly high in these patients (p=0.001). Chronic obstructive pulmonary disease, hypertension and diabetes were significantly related to reduced blood oxygen saturation (p<0.05). Patients with hypertension had significantly raised computerised tomography scores. A significant inverse correlation was found between capillary oxygen saturation and computerised tomography severity index (p<0.01). CONCLUSIONS: A significant inverse correlation was found between capillary oxygen saturation and computerised tomography severity index. Underlying comorbidities also affected the severity index.

Death Be Not Proud: A Commentary on Muslim Acceptance of Death in the Intensive Care Unit.

Technologies used in medicine have meant that treatments can keep people biologically alive but often fail to provide meaningful recovery and quality of life. Many of those from the Islamic faith have relied on these technologies for recovery on religious grounds, even when it may be against clinical advice. This commentary seeks to challenge this notion among many Muslims and suggests there is a psycho-spiritual motivation within the Islamic tradition in not pursuing intensive care treatment that is deemed futile by clinicians. A wish to embrace death in these situations should be expressed to loved ones, and the dying person's loved ones should be encouraged to embrace death, in order to minimise harm from disagreements between clinical staff and family.

The ‘Dual Circulation' development model of China: Background and insights

Purpose>Global supply chains experienced unprecedented changes in 2020 and the relationship between domestic and global markets needed adjustments considering the long-term impacts of the changes that are unfolding around these markets. China has become the first country to announce a formal strategy – "Dual Circulation” Strategy (DCS) – to guide its self-reliant economic development in the post-COVID era. However, what exactly is the DCS and what drove China to publicize this strategy is not yet clear. This study aims to answer these questions.Design/methodology/approach>Based on an extensive review of literature and media reports, a background has been constructed that justifies the DCS as a long-overdue historic necessity.Findings>A novel definition of "Dual Circulation” is introduced. A novel construct to visualize the domestic circulation in light of international and domestic markets and international circulation has been presented. The study argues that maintaining optimum levels of consumption and saving rates is crucial to the DCS's success.Originality/value>The study pioneers the first scientific definition of the "Dual Circulation” that will pave way for future debate on the topic. Also, it is the first time an academic study on the DCS has been executed.

Attitude towards COVID-19 vaccination among healthcare workers: a cross sectional study from Egypt.

BACKGROUND: Herd immunity is necessary to contain the coronavirus disease 2019 (COVID-19) pandemic. Vaccination is the fastest and safest pandemic control strategy. Healthcare workers (HCWs) are essential in providing vaccination information. The aim of this study was to assess intent to be vaccinated against COVID-19 among HCWs in Egypt and to determine the factors that may influence their decision. METHODS: A questionnaire-based cross-sectional study was conducted among HCWs who care for patients in several hospitals in Delta region, Egypt. The questionnaire included sociodemographic, clinical, and occupational data, intention to receive the COVID-19 vaccine, and beliefs and attitudes towards COVID-19 and its vaccination. RESULTS: The study included 455 HCWs with a mean age of 36.55 years (SD = 10.31) and 80% were females. The acceptance rate for the COVID-19 vaccine was 70.5%, while hesitancy and resistancy were both 17.6 and 11.9% respectively. About one-third (33.4%) of the subjects had previously contracted COVID-19. Most participants believed that they had a higher risk of contracting COVID-19 (71.6%). More than 64% believed they were at risk for vaccination side effects. Fear of infection and being at high risk of infection were the main drivers for COVID-19 vaccination, while the major barriers were waiting for additional experience with these new vaccines and having doubts about the vaccines' efficacy. CONCLUSIONS: The acceptance of the COVID-19 vaccination among HCWs is very high. This crucial group needs to be the focus of educational initiatives and campaigns designed to increase public awareness of the safety and effectiveness of COVID-19 vaccination.

Boerhaave’s Syndrome Secondary to Symptomatic COVID-19 Infection

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has infected over 140 million people worldwide (1). COVID-19 symptoms primarily involve the respiratory system. However, recent data suggests that gastrointestinal symptoms occur in 11-61% of cases (2, 3).Boerhaave’s syndrome is a rare and dangerous disorder of the gastrointestinal tract, associated with a mortality rate of up to 50% (4). It most commonly occurs due to a lack of coordination between upper and lower oesophageal sphincters during forceful emesis, leading to an abrupt rise in intra-oesophageal pressures which leads to a transmural tear (5). Less commonly, a tear can be secondary to prolonged coughing (6). The majority of tears occur in the distal posterolateral third of the oesophagus and have an average length of 2.2 cm (7). Risk factors include males, excess alcohol or food consumption (6). We present a case of Boerhaave’s syndrome secondary to prolonged coughing, from COVID-19 infection. The tear was 8 cm in length in the mid anterior oesophagus. The patient survived a major operation and prolonged intensive care stay. Meloy et al. (8) published one case of oesophageal rupture in symptomatic COVID-19 – unfortunately the patient passed away before intervention. Methods A 75-year-old Caucasian female was day seven of COVID-19 infection and had been coping in the community with a continuous dry cough and mild shortness of breath. She presented to Accident and Emergency in the late afternoon when her cough developed into unremitting retching, vomiting, a global headache and epigastric pain disproportionate to presentation. No associated haematemesis or change in bowel habit. Past medical history was significant for hypertension, hypothyroidism, depression and anxiety. Previous surgical history included an open appendicectomy, cholecystectomy and resection of a melanoma. She was previously independent, consumed alcohol socially, a non-smoker and compliant with her regular medications.A CT chest with contrast demonstrated distal oesophageal rupture transversely with pneumomediastinum and extensive surgical emphysema in the neck and secondary bilateral pleural effusions, consistent with Boerhaave’s syndrome. The patient was taken to theatre the next morning for an oesophago-gastro-duodenoscopy (OGD), right posterolateral thoracotomy and primary repair of the oesophageal perforation.On endoscopy, an 8cm defect in the anterior oesophagus starting at the T4 vertebral level was identified and was repaired using tunnelled permanent mesh. During the surgery, mediastinitis was noted and washed out. The antimicrobial therapy was altered post-operatively to intravenous tazocin and fluconazole.  Results The management of this patient was a huge multidisciplinary team achievement. She spent forty-six days recovering in ICU, intubated, ventilated and sedated with noradrenaline vasopressor support. The patient developed a severe acute kidney injury, requiring haemofiltration. The mediastinal fluid culture grew Enterococcus faecalis, sensitive to vancomycin and antibiotic therapy was adjusted accordingly. The patient’s recovery was burdened by seizures, whilst being weaned off sedation, and episodes of bradycardia and asystole, most of which were self-resolving except one requiring thirty seconds of cardio-pulmonary resuscitation. After chest drain removal, the patient redeveloped a right sided loculated pleural effusion so a further drain was inserted.A gastrografin contrast swallow study performed thirty-five days post-operatively demonstrated no evidence of contrast leak although some tracheobronchial aspiration. She was later stepped down to the ward and recovered very well. However, a component of post-ICU delirium and low mood was persistent. The patient had a repeat water-soluble contrast study on day 77 which demonstrated a contained anastomotic leak, managed conservatively. She was deemed medically ready for discharge at day 110. She was readmitted due to dysphagia secondary to a stricture at the site of mesh repair. OGD was performed and a stent was inserted. Conclusions COVID-19 infection may lead to an abnormal presentation of Boerhaave’s syndrome, with oesophageal tears being secondary to coughing, longer and more proximal.Peri-operative morbidity in COVID patients is elevated and clinicians should consider the short and long term implications of this to provide a holistic approach to care. Clinicians should maintain an awareness of the diversity of COVID-associated complications whilst ensuring that they do not succumb to the diagnostic overshadowing that becomes commonplace during a pandemic.

The Severity of Depression, Anxiety, and Stress: Recommendations From Joint Work of Research Center and Psychology Clinics in COVID-19 Pandemic.

The COVID-19 pandemic has significantly affected the psychological stability of general population of Pakistan. However, research on the severity of COVID-19 induced depression, anxiety, and stress (DAS) in Pakistan is scarce. This paper thereby investigates the severity of COVID-19 induced DAS based on demographic, socioeconomic, and personal feeling variables by modeling DAS. Snowball sampling strategy was adopted to conduct online survey from July 03, 2021 to July 09, 2021. Out of 2,442, 2,069 responses from Karachi were included. Descriptive and inferential statistics (binary and multinomial logistic regression analysis) were performed using SPSS V21 (IBM, 2013) to identify significant determinants and their association with DAS severity. The result of this study indicates 27.8, 21.7, and 18.3% respondents suffer from severe and extremely severe states of depression, anxiety, and stress, respectively. Binary logistic regression revealed that age is a significant determinant with odds of having 4.72 (95% CI = 1.86-11.97) and 5.86 (95% CI = 2.26-15.2) times greater depression, and stress for respondents aged 19-26 years. Moreover, gender-based difference is also observed with females 1.34 (95% CI = 1.08-1.68) and 1.75 (95% CI = 1.40-2.20) times more likely to exhibit anxiety and stress than males. Furthermore, marital status is a significant determinant of depression with odds of having depression is 0.67 (95% CI = 0.48-0.93) times greater for married population. Multinomial logistic regression revealed that those who believe COVID-19 pandemic has affected them mentally, fear new COVID-19 cases and deaths, depressed due to imposition of lockdown, believe they will not survive COVID-19 infection, and spend more time on social media gathering COVID-19 updates suffer from extremely severe state of depression (OR mental-effect-of-pandemic = 3.70, OR new-COVID-19-cases-and-deaths = 2.20, OR imposition-of-lockdown = 17.77, OR survival-probability = 8.17, OR time-on-social-media = 9.01), anxiety (OR mental-effect-of-pandemic = 4.78, OR new-COVID-19-cases-and-deaths = 3.52, OR imposition-of-lockdown = 5.06, OR survival-probability = 8.86, OR time-on-social-media = 5.12) and stress (OR mental-effect-of-pandemic = 6.07, OR imposition-of-lockdown = 11.38, OR survival-probability = 15.66, OR time-on-social-media = 4.39). Information regarding DAS severity will serve as a platform for research centers and psychological clinics, to work collectively and provide technology-based treatment to reduce the burden on the limited number of psychologist and psychotherapist.

The relationship between hydroxychloroquine plasma concentration and COVID-19 outcomes in rheumatoid arthritis patients in Saudi Arabia.

Background: The drug hydroxychloroquine (HCQ) is widely used to treat rheumatoid arthritis (RA) and has been repurposed for the treatment of COVID-19. This study aims to determine whether HCQ concentration levels in individuals with RA alter the incidence of COVID-19 or its complications. Methods: We collected plasma samples from 13 individuals with confirmed rheumatoid arthritis (RA) to measure HCQ concentration levels. The study included individuals at least 18 years old who had been taking HCQ for at least six months at daily doses ranging from 200 to 400 mg. Results: The study enrolled a total of 13 RA patients. All patients were chronic HCQ users. Among the 13 patients, 7 patients were receiving HCQ at a dose of 200 mg per day, and 6 patients were receiving HCQ at a dose of 400 mg per day. COVID-19 confirmed cases accounted for approximately 46% of all patients. Half of the infected patients (n = 3) were taking a daily dose of 200 mg daily, while the other half were taking 400 mg daily. COVID-19 symptoms ranged from mild to moderate, and the intensity of the symptoms was not severe enough to necessitate hospitalization. COVID-19 symptoms in RA patients included headache, fever, fatigue, dry cough, and loss of taste or smell. Conclusions: Our findings indicated that there was no correlation between HCQ concentrations in rheumatoid arthritis patients and the occurrence of COVID-19 or its complications.

Immunoinformatics-guided design of a multi-epitope vaccine based on the structural proteins of severe acute respiratory syndrome coronavirus 2† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra02885e

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in a contagious respiratory tract infection that has become a global burden since the end of 2019. Notably, fewer patients infected with SARS-CoV-2 progress from acute disease onset to death compared with the progression rate associated with two other coronaviruses, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Several research organizations and pharmaceutical industries have attempted to develop successful vaccine candidates for the prevention of COVID-19. However, increasing evidence indicates that the SARS-CoV-2 genome undergoes frequent mutation;thus, an adequate analysis of the viral strain remains necessary to construct effective vaccines. The current study attempted to design a multi-epitope vaccine by utilizing an approach based on the SARS-CoV-2 structural proteins. We predicted the antigenic T- and B-lymphocyte responses to four structural proteins after screening all structural proteins according to specific characteristics. The predicted epitopes were combined using suitable adjuvants and linkers, and a secondary structure profile indicated that the vaccine shared similar properties with the native protein. Importantly, the molecular docking analysis and molecular dynamics simulations revealed that the constructed vaccine possessed a high affinity for toll-like receptor 4 (TLR4). In addition, multiple descriptors were obtained from the simulation trajectories, including the root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), and radius of gyration (Rg), demonstrating the rigid nature and inflexibility of the vaccine and receptor molecules. In addition, codon optimization, based on Escherichia coli K12, was used to determine the GC content and the codon adaptation index (CAI) value, which further followed for the incorporation into the cloning vector pET28+(a). Collectively, these findings suggested that the constructed vaccine could be used to modulate the immune reaction against SARS-CoV-2. COVID-19 is caused by SARS-CoV-2, resulting in a contagious respiratory tract infection. For designing a multi-epitope vaccine, we utilized the four structural proteins from the SARS-CoV-2 by using bioinformatics and immunoinformatics analysis.

Effect of chronic hydroxychloroquine use on COVID-19 risk in patients with rheumatoid arthritis and systemic lupus erythematosus: a multicenter retrospective cohort.

OBJECTIVE: Hydroxychloroquine (HCQ) has been used during the coronavirus disease 2019 (COVID-19) pandemic because of its reported anti-viral activity. This study examined the association of chronic HCQ use with the incidence and complications of COVID-19. METHODS: This retrospective cohort study included adults with rheumatoid arthritis and/or systemic lupus erythematosus who visited rheumatology clinics in three tertiary hospitals in Riyadh, Saudi Arabia between January 2019 and December 2020. Patients were categorized into two groups based on HCQ use. Data were obtained from the electronic health record and by interviews with patients. The primary study objective was the incidence of COVID-19 and its complications from March 2020 to February 2021. RESULTS: Almost 11% of the study cohort was positive for COVID-19, and the incidence of COVID-19 was similar between HCQ users (11.11%) and nonusers (10.86%). Disease complication rates were similar in the study arms, and they mainly included fever, dry cough, fatigue, and breathing difficulty. CONCLUSIONS: This study revealed no significant association between chronic HCQ use and the incidence of COVID-19, and disease complications were similar in the study arms.

Emergence, evolution, and vaccine production approaches of SARS-CoV-2 virus: Benefits of getting vaccinated and common questions.

The emergence of coronavirus disease 2019 (COVID-19) pandemic in Wuhan city, China at the end of 2019 made it urgent to identify the origin of the causal pathogen and its molecular evolution, to appropriately design an effective vaccine. This study analyzes the evolutionary background of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or SARS-2) in accordance with its close relative SARS-CoV (SARS-1), which was emerged in 2002. A comparative genomic and proteomic study was conducted on SARS-2, SARS-1, and Middle East respiratory syndrome coronavirus (MERS), which was emerged in 2012. In silico analysis inferred the genetic variability among the tested viruses. The SARS-1 genome harbored 11 genes encoding 12 proteins, while SARS-2 genome contained only 10 genes encoding for 10 proteins. MERS genome contained 11 genes encoding 11 proteins. The analysis also revealed a slight variation in the whole genome size of SARS-2 comparing to its siblings resulting from sequential insertions and deletions (indels) throughout the viral genome particularly ORF1AB, spike, ORF10 and ORF8. The effective indels were observed in the gene encoding the spike protein that is responsible for viral attachment to the angiotensin-converting enzyme 2 (ACE2) cell receptor and initiating infection. These indels are responsible for the newly emerging COVID-19 variants αCoV, ßCoV, γCoV and δCoV. Nowadays, few effective COVID-19 vaccines developed based on spike (S) glycoprotein were approved and become available worldwide. Currently available vaccines can relatively prevent the spread of COVID-19 and suppress the disease. The traditional (killed or attenuated virus vaccine and antibody-based vaccine) and innovated vaccine production technologies (RNA- and DNA-based vaccines and viral vectors) are summarized in this review. We finally highlight the most common questions related to COVID-19 disease and the benefits of getting vaccinated.

The Impact of Disease Control Measures on the Spread of COVID-19 in the Province of Sindh, Pakistan.

The province of Sindh reported the first COVID-19 case in Pakistan on 26th February 2020. The Government of Sindh has employed numerous control measures to limit its spread. However, for low-and middle-income countries such as Pakistan, the management protocols for controlling a pandemic are not always as definitive as they would be in other developed nations. Given the dire socio-economic conditions of Sindh, continuation of province-wise lockdowns may inadvertently cause a potential economic breakdown. By using a data driven SEIR modelling framework, this paper describes the evolution of the epidemic projections because of government control measures. The data from reported COVID-19 prevalence and google mobility is used to parameterize the model at different time points. These time points correspond to the government's call for advice on the prerequisite actions required to curtail the spread of COVID-19 in Sindh. Our model predicted the epidemic peak to occur by 18th June 2020 with approximately 3500 reported cases at that peak, this projection correlated with the actual recorded peak during the first wave of the disease in Sindh. The impact of the governmental control actions and religious ceremonies on the epidemic profile during this first wave of COVID-19 are clearly reflected in the model outcomes through variations in the epidemic peaks. We also report these variations by displaying the trajectory of the epidemics had the control measures been guided differently; the epidemic peak may have occurred as early as the end of May 2020 with approximately 5000 reported cases per day had there been no control measures and as late as August 2020 with only around 2000 cases at the peak had the lockdown continued, nearly flattening the epidemic curve.

Usability and Acceptability of a Mobile App for Behavior Change and to Improve Immunization Coverage among Children in Pakistan: A Mixed-Methods Study.

BACKGROUND: Pakistan's immunization uptake rates are still significantly lower than anticipated despite several initiatives. Lack of awareness, forgetting about vaccination schedule, and vaccine misconception/misinformation are a few of the major drivers that mitigate the rates of immunization. The current COVID-19 pandemic emphasizes the importance of immunization. The significant reductions in regular childhood vaccination during pandemic have increased the risk of outbreaks of vaccine-preventable diseases. Concerns among parents over possibly exposing their children to COVID-19 during child visits may have contributed to the reported declines. Innovative and cost-effective mHealth interventions must be implemented in order to address the problem of inadequate immunization rates. In addition, it is also critical to understand the end user needs in order to reflect on the highly relevant essence of the customized healthcare experience. OBJECTIVE: The aim of this study was to learn about caregivers' attitudes toward the usability and acceptability of behavior-change smartphone applications (mobile phones) for improving immunization coverage in Pakistan. METHODS: A mixed-method design was employed for this study. The study was conducted at Aga Khan University, Hospital. Parents visiting the Community Health Center for 6-week vaccination of their children were recruited. The study was conducted in two stages. Stage 1 consisted of qualitative interviews that grasped the parent's attitudes and challenges to immunization, as well as their acceptability and accessibility of the smartphone-based behavior-change application to increase vaccine uptake. Stage 1 was followed by stage 2, in which data were collected through a questionnaire designed by using data from qualitative interviews. RESULTS: The majority of participants agreed that immunization serves an important role in protecting their child from illnesses that cause morbidity and mortality. Almost all of them emphasized the importance of using a pre-appointment method at vaccination center in order to reduce the waiting time. Furthermore, participants were also interested in AI-based behavior modification applications related to immunization. They also wanted to have applications in their native language for better understanding and communication of related information. In our study, approximately 95.2 percent of participants agreed to accept SMS immunization updates, which was also reasonably high. Lastly, the majority of them identified forgetfulness as a significant contributor to regular immunization. CONCLUSION: To enhance the uptake of childhood vaccines, overall vaccination rates, and overcome barriers related to vaccination coverage, cost-effective and user-friendly mHealth AI-based smart phone applications are required to raise awareness regarding the continuation of vaccination service and the importance of timely vaccination. Parents' experiences and attitudes must be considered while designing and evaluating the efficacy of mHealth-based interventions.

Phytochemicals from Leucas zeylanica Targeting Main Protease of SARS-CoV-2: Chemical Profiles, Molecular Docking, and Molecular Dynamics Simulations.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a contemporary coronavirus, has impacted global economic activity and has a high transmission rate. As a result of the virus's severe medical effects, developing effective vaccinations is vital. Plant-derived metabolites have been discovered as potential SARS-CoV-2 inhibitors. The SARS-CoV-2 main protease (Mpro) is a target for therapeutic research because of its highly conserved protein sequence. Gas chromatography-mass spectrometry (GC-MS) and molecular docking were used to screen 34 compounds identified from Leucas zeylanica for potential inhibitory activity against the SARS-CoV-2 Mpro. In addition, prime molecular mechanics-generalized Born surface area (MM-GBSA) was used to screen the compound dataset using a molecular dynamics simulation. From molecular docking analysis, 26 compounds were capable of interaction with the SARS-CoV-2 Mpro, while three compounds, namely 11-oxa-dispiro[4.0.4.1]undecan-1-ol (-5.755 kcal/mol), azetidin-2-one 3,3-dimethyl-4-(1-aminoethyl) (-5.39 kcal/mol), and lorazepam, 2TMS derivative (-5.246 kcal/mol), exhibited the highest docking scores. These three ligands were assessed by MM-GBSA, which revealed that they bind with the necessary Mpro amino acids in the catalytic groove to cause protein inhibition, including Ser144, Cys145, and His41. The molecular dynamics simulation confirmed the complex rigidity and stability of the docked ligand-Mpro complexes based on the analysis of mean radical variations, root-mean-square fluctuations, solvent-accessible surface area, radius of gyration, and hydrogen bond formation. The study of the postmolecular dynamics confirmation also confirmed that lorazepam, 11-oxa-dispiro[4.0.4.1]undecan-1-ol, and azetidin-2-one-3, 3-dimethyl-4-(1-aminoethyl) interact with similar Mpro binding pockets. The results of our computerized drug design approach may assist in the fight against SARS-CoV-2.

A molecular modelling approach for identifying antiviral selenium-containing heterocyclic compounds that inhibit the main protease of SARS-CoV-2: an in silico investigation.

Coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic by the World Health Organization, and the situation worsens daily, associated with acute increases in case fatality rates. The main protease (Mpro) enzyme produced by SARS-CoV-2 was recently demonstrated to be responsible for not only viral reproduction but also impeding host immune responses. The element selenium (Se) plays a vital role in immune functions, both directly and indirectly. Thus, we hypothesised that Se-containing heterocyclic compounds might curb the activity of SARS-CoV-2 Mpro. We performed a molecular docking analysis and found that several of the selected selenocompounds showed potential binding affinities for SARS-CoV-2 Mpro, especially ethaselen (49), which exhibited a docking score of -6.7 kcal/mol compared with the -6.5 kcal/mol score for GC376 (positive control). Drug-likeness calculations suggested that these compounds are biologically active and possess the characteristics of ideal drug candidates. Based on the binding affinity and drug-likeness results, we selected the 16 most effective selenocompounds as potential anti-COVID-19 drug candidates. We also validated the structural integrity and stability of the drug candidate through molecular dynamics simulation. Using further in vitro and in vivo experiments, we believe that the targeted compound identified in this study (ethaselen) could pave the way for the development of prospective drugs to combat SARS-CoV-2 infections and trigger specific host immune responses.