Identification of potent COVID-19 main protease inhibitors by loading of favipiravir on Mg12O12 and Zn12O12 nanoclusters: an in silico strategy for COVID-19 treatment.

Pandemic new severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has increased throughout the world. There is no effective treatment against this virus until now. Since its appearance in Wuhan, China in December 2019, SARS-CoV-2 becomes the largest challenge the world is opposite today, including the discovery of an antiviral drug for this virus. Several viral proteins have been prioritized as SARS-CoV-2 antiviral drug targets, among them the papain-like protease (PLpro) and the main protease (Mpro). Inhibition of these proteases would target viral replication, viral maturation and suppression of host innate immune responses. Potential candidates have been identified to show inhibitory effects against Mpro, both in biochemical assays and viral replication in cells. There are different molecules such as lopinavir and favipiravir considerably inhibit the activity of Mpro in vitro. Different studies have shown that structurally improved favipiravir and other similar compounds can inhibit SARS-CoV-2 main protease. In this work, we study the interactions between favipiravir with Mg12O12 and Zn12O12 nanoclusters by density functional theory (DFT) and quantum mechanics atoms in molecules (QMAIM) methods to summarize the ability to load favipiravir onto Mg12O12 and Zn12O12 nanoclusters. Favipiravir-Mg12O12 and favipiravir-Zn12O12 lowest structures complexes were chosen to dock inside the SARS-CoV-2 main protease by molecular docking study. The molecular docking analysis revealed that the binding affinity of Mg12O12 and Zn12O12 nanoclusters inside the Mpro receptor is larger than that of favipiravir. Also, the loading of favipiravir on the surface of Mg12O12 and Zn12O12 nanoclusters increased the binding affinity against the Mpro receptor. Subsequently, 100 ns molecular dynamics simulation of the favipiravir-Mg12O12, and favipiravir-Zn12O12 docked inside the Mpro complexes established that favipiravir-Mg12O12, forms the most stable complex with the Mpro. Further molecular mechanics Poisson Boltzmann surface area (MMPBSA) analyses using the MD trajectories also demonstrated the higher binding affinity of favipiravir-Mg12O12 inside the Mpro. In summary, this study demonstrates a new way to characterize leads for novel anti-viral drugs against SARS-CoV-2, by improving the drug ability of favipiravir via loading it on Mg12O12 and Zn12O12 nanoclusters.Communicated by Ramaswamy H. Sarma.

Impact of Prolonged COVID-19 Lockdown on Body Mass Index, Eating Habits, and Physical Activity of University Students in Bangladesh: A Web-Based Cross-Sectional Study.

Objectives: This current study aims to assess the prevalence and factors associated with body mass index (BMI), dietary patterns, and the extent of physical activities among university students following the prolonged coronavirus disease 2019 (COVID-19) lockdown in Bangladesh. Methods: A cross-sectional web-based survey was conducted between July 10 to August 10, 2021, through a pre-designed Google Form to collect the data from Bangladeshi university students (age: ≥18 years). Informed consent was electronically obtained from each participant, and a simple snowball technique was employed during the sampling. Frequency and percentage distribution, paired t-test, chi-square [χ2] test, and multinomial and binary logistic regression analyses were consecutively applied to analyze the collected data. Results: Among the total participants (n = 1,602), 45.1% were female and 55.6% were 22-25 years' age group students. The BMI (mean ± standard deviation, SD) during the COVID-19 lockdown was 23.52 ± 7.68 kg/m2, which was 22.77 ± 4.11 kg/m2 during the pre-lockdown period (mean difference = 0.753; p < 0.001). The multinomial logistic regression analysis found a significant impact of gender [male vs. female: adjusted relative risk ratio (RRR) = 1.448; 95% confidence interval (CI) = 1.022, 2.053; p = 0.037], age (years) (<22 vs. >25: RRR =0.389, 95% CI = 0.213,0.710; p = 0.002, and 22-25 vs. >25: RRR = 0.473, 95% CI = 0.290, 0.772; p = 0.003), monthly family income (BDT) (<25,000 vs. >50,000: RRR = 0.525, 95% CI = 0.334,0.826; p = 0.005), university type (public vs. private: RRR = 0.540, 95% CI = 0.369, 0.791; p = 0.002), eating larger meals/snacks (increased vs. unchanged: RRR = 2.401, 95% CI = 1.597, 3.610; p < 0.001 and decreased vs. unchanged: RRR = 1.893, 95% CI = 1.218, 2.942; p = 0.005), and verbally or physically abuse (yes vs. no: RRR = 1.438, 95% CI = 0.977, 2.116; p = 0.066) on obesity during COVID-19 pandemic. Besides, the female students and those who have constant eating habits, were more likely to be underweight. Additionally, the binary logistic regression analysis found that the students from private universities [others vs. private: adjusted odds ratio (AOR) = 0.461, 95% CI = 0.313, 0.680; p < 0.001], urban areas (urban vs. rural: AOR = 1.451, 95% CI = 1.165, 1.806; p = 0.001), wealthier families (<25,000 BDT vs. >50,000 BDT: AOR = 0.727, 95% CI = 0.540, 0.979; p = 0.036), and who were taking larger meals/snacks (increased vs. unchanged: AOR = 2.806, 95% CI = 2.190, 3.596; p < 0.001) and had conflicts/arguments with others (no vs. yes: AOR = 0.524, 95% CI = 0.418, 0.657; p < 0.001), were significantly more physically inactive. Finally, the level of education and smoking habits significantly influenced the eating habits of university students during the extended strict lockdown in Bangladesh. Conclusion: The current findings would be helpful tools and evidence for local and international public health experts and policymakers to reverse these worsening effects on students mediated by the prolonged lockdown. Several effective plans, programs, and combined attempts must be earnestly implemented to promote a smooth academic and daily life.

In Silico Evaluation of Different Flavonoids from Medicinal Plants for Their Potency against SARS-CoV-2

The ongoing pandemic situation of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global threat to both the world economy and public health. Therefore, there is an urgent need to discover effective vaccines or drugs to fight against this virus. The flavonoids and their medicinal plant sources have already exhibited various biological effects, including antiviral, anti-inflammatory, antioxidant, etc. This study was designed to evaluate different flavonoids from medicinal plants as potential inhibitors against the spike protein (Sp) and main protease (Mpro) of SARS-CoV-2 using various computational approaches such as molecular docking, molecular dynamics. The binding affinity and inhibitory effects of all studied flavonoids were discussed and compared with some antiviral drugs that are currently being used in COVID-19 treatment namely favipiravir, lopinavir, and hydroxychloroquine, respectively. Among all studies flavonoids and proposed antiviral drugs, luteolin and mundulinol exhibited the highest binding affinity toward Mpro and Sp. Drug-likeness and ADMET studies revealed that the chosen flavonoids are safe and non-toxic. One hundred ns-MD simulations were implemented for luteolin-Mpro, mundulinol-Mpro, luteolin-Sp, and mundulinol-Sp complexes and the results revealed strong stability of these flavonoid-protein complexes. Furthermore, MM/PBSA confirms the stability of luteolin and mundulinol interactions within the active sites of this protein. In conclusion, our findings reveal that the promising activity of luteolin and mundulinol as inhibitors against COVID-19 via inhibiting the spike protein and major protease of SARS CoV-2, and we urge further research to achieve the clinical significance of our proposed molecular-based efficacy.

Design of a multi-epitope vaccine against SARS-CoV-2: immunoinformatic and computational methods† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra06532g

A novel infectious agent, SARS-CoV-2, is responsible for causing the severe respiratory disease COVID-19 and death in humans. Spike glycoprotein plays a key role in viral particles entering host cells, mediating receptor recognition and membrane fusion, and are considered useful targets for antiviral vaccine candidates. Therefore, computational techniques can be used to design a safe, antigenic, immunogenic, and stable vaccine against this pathogen. Drawing upon the structure of the S glycoprotein, we are trying to develop a potent multi-epitope subunit vaccine against SARS-CoV-2. The vaccine was designed based on cytotoxic T-lymphocyte and helper T-lymphocyte epitopes with an N-terminal adjuvant via conducting immune filters and an extensive immunoinformatic investigation. The safety and immunogenicity of the designed vaccine were further evaluated via using various physicochemical, allergenic, and antigenic characteristics. Vaccine-target (toll-like receptors: TLR2 and TLR4) interactions, binding affinities, and dynamical stabilities were inspected through molecular docking and molecular dynamic (MD) simulation methods. Moreover, MD simulations for dimeric TLRs/vaccine in the membrane-aqueous environment were performed to understand the differential domain organization of TLRs/vaccine. Further, dynamical behaviors of vaccine/TLR systems were inspected via identifying the key residues (named HUB nodes) that control interaction stability and provide a clear molecular mechanism. The obtained results from molecular docking and MD simulation revealed a strong and stable interaction between vaccine and TLRs. The vaccine's ability to stimulate the immune response was assessed by using computational immune simulation. This predicted a significant level of cytotoxic T cell and helper T cell activation, as well as IgG, interleukin 2, and interferon-gamma production. This study shows that the designed vaccine is structurally and dynamically stable and can trigger an effective immune response against viral infections. SARS-CoV-2 infections have spread throughout the world and became a rapidly emerging public health issue. The immunoinformatics approach was applied to design a potent multi-epitope vaccine against this deadly virus.

Factors Associated With Underprivileged E-Learning, Session Jam Phobia, and the Subsequent Mental Distress Among Students Following the Extended University Closure in Bangladesh.

Severe session jam phobia (SJP), the extent of underprivileged online education, and subsequent mental health disorders among students have emerged as distinguished global problems due to the overwhelming effects of coronavirus disease 2019 (COVID-19). The purpose of this research was to evaluate the impact of extended COVID-19 lockdown and its mediating factors on current e-Learning activities, the prevalence of severe SJP and psychological distress among university students in Bangladesh. A web-based cross-sectional study was conducted to assemble responses through Google Form by applying a simple snowball sampling technique among university students aged 18 years or above in Bangladesh. All ethical considerations were maintained, and univariate, bivariate, and multivariate analyses were employed to analyze the acquired data set. Among the total analyzed data (n = 1,122), the male and female ratio was almost 1:1, and a remarkable segment (63.7%) was aged between 21-24 years. Alarmingly, around 50-60% of the students were suffering from severe SJP, prevailing underprivileged education in the e-Learning platform, and severe mental distress. Logistic regression analyses demonstrated that the students from public universities, lower- and mid-income families, lower-aged, and junior years education groups were significantly (p < 0.05) more underprivileged than their counter groups. Besides, the monthly family income and university type significantly influenced the extent of severe SJP. Finally, the students who were female, rustic, come from low-income families (below 25,000 BDT), who had academic uncertainty, job insecurity, online exam phobia, and dissatisfaction with e-Learning education, were significantly suffering from moderate to severe mental distress. The current evidence demonstrates that a substantial number of Bangladeshi university students are struggling with extreme session jam phobia, underprivileged e-Learning education, and subsequent psychological distress, which need to be immediately addressed through concerted efforts by the government, parents, and university authorities.

Design of a multi-epitope vaccine against SARS-CoV-2: immunoinformatic and computational methods.

A novel infectious agent, SARS-CoV-2, is responsible for causing the severe respiratory disease COVID-19 and death in humans. Spike glycoprotein plays a key role in viral particles entering host cells, mediating receptor recognition and membrane fusion, and are considered useful targets for antiviral vaccine candidates. Therefore, computational techniques can be used to design a safe, antigenic, immunogenic, and stable vaccine against this pathogen. Drawing upon the structure of the S glycoprotein, we are trying to develop a potent multi-epitope subunit vaccine against SARS-CoV-2. The vaccine was designed based on cytotoxic T-lymphocyte and helper T-lymphocyte epitopes with an N-terminal adjuvant via conducting immune filters and an extensive immunoinformatic investigation. The safety and immunogenicity of the designed vaccine were further evaluated via using various physicochemical, allergenic, and antigenic characteristics. Vaccine-target (toll-like receptors: TLR2 and TLR4) interactions, binding affinities, and dynamical stabilities were inspected through molecular docking and molecular dynamic (MD) simulation methods. Moreover, MD simulations for dimeric TLRs/vaccine in the membrane-aqueous environment were performed to understand the differential domain organization of TLRs/vaccine. Further, dynamical behaviors of vaccine/TLR systems were inspected via identifying the key residues (named HUB nodes) that control interaction stability and provide a clear molecular mechanism. The obtained results from molecular docking and MD simulation revealed a strong and stable interaction between vaccine and TLRs. The vaccine's ability to stimulate the immune response was assessed by using computational immune simulation. This predicted a significant level of cytotoxic T cell and helper T cell activation, as well as IgG, interleukin 2, and interferon-gamma production. This study shows that the designed vaccine is structurally and dynamically stable and can trigger an effective immune response against viral infections.

A Comprehensive Overview of the Newly Emerged COVID-19 Pandemic: Features, Origin, Genomics, Epidemiology, Treatment, and Prevention

The coronavirus disease 2019 (COVID-19), a life-threatening pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has resulted in massive destruction and is still continuously adding to its death toll. The advent of this global outbreak has not yet been confirmed;however, investigation for suitable prophylaxis against this lethal virus is being carried out by experts all around the globe. The SARS-CoV-2 belongs to the Coronaviridae superfamily, like the other previously occurring human coronavirus variants. To better understand a new virus variant, such as the SARS-CoV-2 delta variant, it is vital to investigate previous virus strains, including their genomic composition and functionality. Our study aimed at addressing the basic overview of the virus’ profile that may provide the scientific community with evidence-based insights into COVID-19. Therefore, this study accomplished a comprehensive literature review that includes the virus’ origin, classification, structure, life cycle, genome, mutation, epidemiology, and subsequent essential factors associated with host–virus interaction. Moreover, we summarized the considerable diagnostic measures, treatment options, including multiple therapeutic approaches, and prevention, as well as future directions that may reduce the impact and misery caused by this devastating pandemic. The observations and data provided here have been screened and accumulated through extensive literature study, hence this study will help the scientific community properly understand this new virus and provide further leads for therapeutic interventions.

Clinical Efficacy and Safety of Antiviral Drugs in the Extended Use against COVID-19: What We Know So Far

Human beings around the globe have been suffering from a devastating novel pandemic and public health emergency, coronavirus disease 2019 (COVID-19), for more than one and a half years due to the deadly and highly pathogenic severe acute respiratory coronavirus 2 (SARS-CoV-2) infection worldwide. Notably, no effective treatment strategy has been approved for the complete recovery of COVID-19 patients, though several vaccines have been rolled out around the world upon emergency use authorization. After the emergence of the COVID-19 outbreak globally, plenty of clinical investigations commenced to screen the safety and efficacy of several previously approved drugs to be repurposed against the SARS-CoV-2 pathogen. This concise review aims at exploring the current status of the clinical efficacy and safety profile of several antiviral medications for the treatment of patients with COVID-19 and other respiratory complications caused by SARS-CoV-2 infection. The paper covers all kinds of human studies (January 2020 to June 2021) except case reports/series to highlight the clear conclusion based on the current clinical evidence. Among the promising repositioned antivirals, remdesivir has been recommended in critical conditions to mitigate the fatality rate and improve clinical conditions. In addition, boosting the immune system is believed to be beneficial in treating COVID-19 patients, so interferon type I might exert immunomodulation through its antiviral effects by stimulating interferon-stimulated gene (ISG). However, more extensive clinical studies covering all ethnic groups globally are warranted based on current data to better understand the clinical efficacy of the currently proposed repurposed drugs against COVID-19.

Designing a multi-epitope vaccine candidate to combat MERS-CoV by employing an immunoinformatics approach.

Currently, no approved vaccine is available against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes severe respiratory disease. The spike glycoprotein is typically considered a suitable target for MERS-CoV vaccine candidates. A computational strategy can be used to design an antigenic vaccine against a pathogen. Therefore, we used immunoinformatics and computational approaches to design a multi-epitope vaccine that targets the spike glycoprotein of MERS-CoV. After using numerous immunoinformatics tools and applying several immune filters, a poly-epitope vaccine was constructed comprising cytotoxic T-cell lymphocyte (CTL)-, helper T-cell lymphocyte (HTL)-, and interferon-gamma (IFN-γ)-inducing epitopes. In addition, various physicochemical, allergenic, and antigenic profiles were evaluated to confirm the immunogenicity and safety of the vaccine. Molecular interactions, binding affinities, and the thermodynamic stability of the vaccine were examined through molecular docking and dynamic simulation approaches, during which we identified a stable and strong interaction with Toll-like receptors (TLRs). In silico immune simulations were performed to assess the immune-response triggering capabilities of the vaccine. This computational analysis suggested that the proposed vaccine candidate would be structurally stable and capable of generating an effective immune response to combat viral infections; however, experimental evaluations remain necessary to verify the exact safety and immunogenicity profile of this vaccine.

Combination of QSAR, molecular docking, molecular dynamic simulation and MM-PBSA: analogues of lopinavir and favipiravir as potential drug candidates against COVID-19.

Pandemic COVID-19 infections have spread throughout the world. There is no effective treatment against this disease. Viral RNA-dependent RNA polymerase (RdRp) catalyzes the replication of RNA from RNA and the main protease (Mpro) has a role in the processing of polyproteins that are translated from the RNA of SARS-CoV-2, and thus these two enzymes are strong candidates for targeting by anti-viral drugs. Small molecules such as lopinavir and favipiravir significantly inhibit the activity of Mpro and RdRp in vitro. Studies have shown that structurally modified lopinavir, favipiravir, and other similar compounds can inhibit COVID-19 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). In this study, lopinavir and its structurally similar compounds were chosen to bind the main protease, and favipiravir was chosen to target RNA-dependent RNA polymerase. Molecular docking and the quantitative structure-activity relationships (QSAR) study revealed that the selected candidates have favorable binding affinity but less druggable properties. To improve the druggability, four structural analogues of lopinavir and one structural analogue of favipiravir was designed by structural modification. Molecular interaction analyses have displayed that lopinavir and favipiravir analogues interact with the active site residues of Mpro and RdRp, respectively. Absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, medicinal chemistry profile, and physicochemical features were shown that all structurally modified analogues are less toxic and contain high druggable properties than the selected candidates. Subsequently, 50 ns molecular dynamics simulation of the top four docked complexes demonstrated that CID44271905, a lopinavir analogue, forms the most stable complex with the Mpro. Further MMPBSA analyses using the MD trajectories also confirmed the higher binding affinity of CID44271905 towards Mpro. In summary, this study demonstrates a new way to identify leads for novel anti-viral drugs against COVID-19. Communicated by Ramaswamy H. Sarma.