ABSTRACT
AJOL : This study is carried out to find novel active drug candidates which can effectively bind to key residues of main protease (Mpro) of SARSCoV-2. We performed molecular docking of fifty-seven (57) ligands from two classes: vanillylacetone and its derivatives and beta-hydroxy ketone derivatives against Mpro of SARS-CoV-2. We also docked three antiviral drugs as reference/benchmark drugs including remdesivir (RDV), chloroquine (CQ), and hydroxychloroquine (HCQ) against Mpro for comparison of inhibition tendencies of selected ligands. Binding energies of our reference drugs are as: CQ = -5.1 kcal mol-1 (with predicted inhibition constant (Ki pred) = 177 µmol), HCQ = -5.7 kcal mol-1 (Ki pred = 64.07 µmol) and RDV -6.3 kcal mol-1 (Ki pred = 13.95 µmol). We got remarkable results for our docked ligands as 79% of total ligands indicated binding energies better than CQ, 39 % better than both HCQ and CQ, and 19 % better than all reference drugs. More interestingly interaction analysis of eight best-docked ligands showed that they interacted with desired key residues of Mpro. We further selected the four best-docked ligands L1 = -6.6 kcal mol-1 (Ki pred =13.95 µmol), L6 = -7.0 kcal mol-1 (Ki pred = 7.08 µmol), L34 = -6.0 kcal mol-1 (Ki pred = 38.54 µmol), and L50 = -6.6 kcal mol-1 (Ki pred =13.95 µmol) for further analysis by quantum chemical study, molecular dynamic (MD) simulations and ADMET analysis. We have also carried out MD-simulations of six more docked ligand L2, L14, L20, L36, L46 and L48 some of which were showing weak binding affinities and some average binding affinities to check their simulation behavior. Their RMSD, RMSF and binding free energy results were also quite satisfying. We believe the current investigation will evoke the scientific community and highlights the potential of selected compounds for potential use as antiviral compounds against Mpro of SARS-CoV-2
ABSTRACT
BACKGROUND: The ongoing outbreak of SARS-CoV-2 represents a significant challenge to international health. Several reports have highlighted the importance of ACE2 on the pathogenesis of COVID-19. The spike protein of SARS-CoV-2 efficiently binds to the angiotensin-converting enzyme 2 (ACE2) receptors and facilitates virus entry into the host cell. In the present study, we hypothesize that a functional insertion/deletion polymorphism-rs4646994 I/D and rs4240157 T > C in the ACE gene could be associated with SARS-CoV-2 infection and mortality. METHODOLOGY: This study included 117 consecutive COVID-19 patients and 150 age matched healthy controls (ACE2-rs4646994 I/D) and 100 age matched healthy controls with ACE2 rs4240157 T > C. We used Mutation specific PCR (MSP) for ACE2-rs4646994 I/D genotyping and amplification refractory mutation system (ARMS-PCR) for ACE2 rs4240157 T > C genotyping. RESULTS: Results indicated that there were significant differences in the genotype distributions of ACE2-rs4646994 I/D polymorphisms (p < 0.030) and ACE2 rs4240157 T > C between COVID-19 patients and controls (p-values < 0.05). Higher frequency of DD genotype (48.71%) and D allele (0.67) was reported in COVID-19 patients than controls. Our results showed that the ACE2-DD genotype was strongly associated with increased COVID-19 severity (OR 2.37 (95%) CI = (1.19-4.70), RR = 1.39 (1.09-1.77), p < 0.013) and also a strong association was seen with ACE2-ID genotype with COVID-19 severity (OR 2.20 (95%) CI = (1.08-4.46), p < 0.020) in the codominant model. In allelic comparison, the D allele was strongly associated with COVID-19 severity (OR 1.58 (95% CI) (1.11-2.27), RR 1.21 (1.05-1.41) p < 0.010). A significant correlation of ACE2-I/D genotypes was reported with Age (p < 0.035), T2D (p < 0.0013), hypertension (p < 0.0031) and coronary artery disease (p < 0.0001). Our results indicated ACE2-DD genotype was strongly associated with increased COVID-19 mortality (OR 8.25 (95%) CI = (2.40 to 28.34), p < 0.008) and also ACE2-DD + DI genotype was strongly associated with increased COVID-19 mortality with OR 4.74 (95%) CI = (1.5214 to 14.7915), p < 0.007. A significant correlation was reported between COVID-19 patients and age matched controls (p < 0.0007). Higher frequency of heterozygosity TC (40%) followed by ACE2-CC genotype (24.78%) was reported among COVID-19 patients. Using multivariate analysis, ACE2-CT genotype was strong associated with SARS-CoV-2 severity with an OR 2.18 (95% CI) (1.92-3.99), p < 0.010 and also ACE2-CC genotype was linked with COVID-19 severity with an OR 2.66 (95% CI) (1.53-4.62), p < 0.005. A significant correlation of ACE2-T > C genotypes was reported with gender (p < 0.04), T2D (p < 0.035). ACE2-CC genotype was strongly associated with increased COVID-19 mortality OR 3.66 (95%) CI = (1.34 to 9.97), p < 0.011 and also ACE2-C allele was associated with COVID-19 mortality OR 2, 01 (1.1761-3.45), p < 0.010. CONCLUSIONS: It is concluded that ACE-DD genotype and D allele was strongly associated with increased COVID-19 patient severity. In addition, ACE I/D polymorphism were strongly associated with advanced age, diabetes and ischemic heart disease in COVID-19 patients whereas ACE-II genotype was a protective factor against the development of severe COVID-19. ACE2-DD genotype was strongly associated with increased COVID-19 mortality. Additionally, ACE2-CC and CT genotypes were strongly associated with COVID-19 severity. Therefore, our study might be useful for identifying the susceptible population groups for targeted interventions and for making relevant public health policy decisions.
ABSTRACT
Background: Viral infections such as measles virus (MV), herpes virus, and human immunodeficiency virus (HIV) can lead to transient or permanent neurological or psychiatric dysfunction. However, respiratory system affecting viruses have appeared as an unbeatable challenge to the modern world. They include the human respiratory syncytial virus (hRSV), the influenza virus (IV), and the coronavirus (CoV). They cause acute respiratory infections mainly children under 5 years old and also the elderly. The most frequent clinical manifestations are febrile or afebrile seizures, status epilepticus, encephalopathies, and encephalitis. Objective: The objective of this review is to assess the effect of COVID-19 on our mood and thinking during this pandemic. Method: We reviewed the literature using different databases e.g., Google Scholar, PubMed, and Science direct etc. Results: Viral Infections badly affect the nervous system functions and ultimate can lead to the onset of neurological and psychological illnesses. Conclusion: COVID-19 is somehow causing depression, anxiety, panic attacks, and stress. As a consequence, social distancing has increased that has ultimately modified our thinking style, mood and has lead to the psychological, emotional and behavioral changes. Review Criteria We reviewed the literature using different databases e.g., Google Scholar, PubMed, etc. from 1997 to 2021 without language limitations. Message for the clinic It is clear that COVID-19 causes cardiac, respiratory, renal, and gastrointestinal dysfunctions and has also a direct effect on brain functioning resulting in psychological and behavioral changes. Along with other dysfunctions, it has severely affected the living style of people and brought depression, anxiety, panic attacks, loneliness, and self-deprecation. It is highly recommended that while treating such patients, all these aspects should be kept in mind. Hence, not only medication can ameliorate the side impacts of this infection but counseling is another tool to bring positive impact in those respondents.