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1.
Int J Gen Med ; 15: 4907-4916, 2022.
Article in English | MEDLINE | ID: covidwho-1855199

ABSTRACT

Background: Cytokine release syndrome (CRS) significantly contributes to the pathophysiology and progression of COVID-19. It is speculated that therapeutic plasma exchange (TPE) can dampen CRS via elimination of pathogenic cytokines. Objectives: The study is intended to compare the outcomes of COVID-19 patients with CRS treated with TPE and standard care (SC) to their counterparts receiving SC alone. Methodology: A retrospective cohort study of severe COVID-19 confirmed patients presenting with CRS and admitted to the medical ICU was conducted between March and August 2021. Using case-control (CC) matching 1:1, 162 patients were selected and divided into two equal groups. The primary outcome was 28-day in-hospital survival analysis in severe COVID-19 patients with CRS. However, secondary outcomes included the effect of plasmapheresis on inflammatory markers, the need for mechanical ventilation, the rate of extubation, and the duration of survival. Results: After CC matching, the study cohort had a mean age of 55.41 (range 56.41±11.56 in TP+SC and 54.42±8.94 in SC alone; p=0.22). There were 25.95% males and 74.05% females in both groups. The mean time from first day of illness to hospitalization was 6.53±2.18 days. The majority of patients with CRS had comorbid conditions (75.9%). Diabetes mellitus was the most common comorbidity (40.1%), followed by hypertension (25.3%), and chronic kidney disease (21%). Notable reduction in some inflammatory markers (D-dimers, LDH, CRP and serum ferritin) (p<0.0001) was observed in the group that received TPE+SC. Moreover, the patients in the plasmapheresis plus standard care group required relatively less mechanical ventilation as compared to the group receiving SC alone (46.9% vs 58.1%, respectively; p>0.05). The rate of extubation in the TP+SC group vs SC alone was 60.5% vs 44.7%, respectively (p>0.05). Similarly, the mortality percentages in both groups were 19.8% and 24.7%, respectively. Conclusion: For this particular group of matched patients with COVID-19-induced CRS, TPE+SC was linked with relatively better overall survival, early extubation, and earlier discharge compared to SC alone. As these results were not statistically significant, multi-centered randomized control trials are needed to further elaborate the role of therapeutic plasmapheresis in COVID-19 induced CRS.

2.
Molecules ; 27(7)2022 Apr 06.
Article in English | MEDLINE | ID: covidwho-1776294

ABSTRACT

The continued emergence of human coronaviruses (hCoVs) in the last few decades has posed an alarming situation and requires advanced cross-protective strategies against these pandemic viruses. Among these, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), and Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) have been highly associated with lethality in humans. Despite the challenges posed by these viruses, it is imperative to develop effective antiviral therapeutics and vaccines for these human-infecting viruses. The proteomic similarity between the receptor-binding domains (RBDs) among the three viral species offers a potential target for advanced cross-protective vaccine designs. In this study, putative immunogenic epitopes including Cytotoxic T Lymphocytes (CTLs), Helper T Lymphocytes (HTLs), and Beta-cells (B-cells) were predicted for each RBD-containing region of the three highly pathogenic hCoVs. This was followed by the structural organization of peptide- and mRNA-based prophylactic vaccine designs. The validated 3D structures of these epitope-based vaccine designs were subjected to molecular docking with human TLR4. Furthermore, the CTL and HTL epitopes were processed for binding with respective human Lymphocytes Antigens (HLAs). In silico cloning designs were obtained for the prophylactic vaccine designs and may be useful in further experimental designs. Additionally, the epitope-based vaccine designs were evaluated for immunogenic activity through immune simulation. Further studies may clarify the safety and efficacy of these prophylactic vaccine designs through experimental testing against these human-pathogenic coronaviruses.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevention & control , Epitopes, B-Lymphocyte , Epitopes, T-Lymphocyte , Humans , Molecular Docking Simulation , Proteomics , RNA, Messenger , Vaccines, Subunit/chemistry , Vaccinology
3.
Antibiotics (Basel) ; 11(2)2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1649138

ABSTRACT

(1) Background: Immune compromised hemodialysis patients are more likely to develop COVID-19 infections, which increase the risk of mortality. The benefits of Remdesivir, despite less literature support on its effectiveness in dialysis patients due to renal toxicity, can outweigh the risks if prescribed early. The aim of this study was to evaluate the efficacy of Remdesivir on the 30-day in-hospital clinical outcome of hemodialysis population with COVID-19 infection and safety endpoints of adverse events. (2) Study design: A prospective quasi-experimental study design was used in the study. (3) Methods: The sample population consisted of 83 dialysis patients with COVID-19 who were administered Remdesivir at a dose of 100 mg before hemodialysis, as per hospital protocol. After the treatment with Remdesivir, we assessed the outcomes across two endpoints, namely primary (surviving vs. dying) as well as clinical and biochemical changes (ferritin, liver function test, C-reactive protein, oxygen requirements, and lactate dehydrogenase levels) and secondary (adverse effects, such as diarrhea, rise in ALT). In Kaplan-Meier analysis, the survival probabilities were compared between patients who received Remdesivir within 48 h of diagnosis and those who received it after 48 h. Cox regression analysis was employed to determine the predictors of outcome. (4) Results: Of the 83 patients, 91.5% survived and 8.4% died. Remdesivir administration did not reduce the death rate overall. Hospital stays were shorter (p = 0.03) and a nasopharyngeal swab for COVID-19 was negative earlier (p = 0.001) in survivors who had received Remdesivir within 48 h of diagnosis compared to those who had received Remdesivir after 48 h. The only variables linked to the 30-day mortality were serum CRP (p = 0.028) and TLC (p = 0.013). No major adverse consequences were observed with Remdesivir. (5) Conclusions: Remdesivir has the potential to shorten the recovery time for dialysis patients if taken within 48 h of onset of symptoms, without any adverse effects.

4.
Int J Biol Macromol ; 200: 438-448, 2022 Mar 01.
Article in English | MEDLINE | ID: covidwho-1633972

ABSTRACT

As SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) continues to inflict chaos globally, a new variant officially known as B.1.1.529 was reported in South Africa and was found to harbor 30 mutations in the spike protein. It is too early to speculate on transmission and hospitalizations. Hence, more analyses are required, particularly to connect the genomic patterns to the phenotypic attributes to reveal the binding differences and antibody response for this variant, which can then be used for therapeutic interventions. Given the urgency of the required analysis and data on the B.1.1.529 variant, we have performed a detailed investigation to provide an understanding of the impact of these novel mutations on the structure, function, and binding of RBD to hACE2 and mAb to the NTD of the spike protein. The differences in the binding pattern between the wild type and B.1.1.529 variant complexes revealed that the key substitutions Asn417, Ser446, Arg493, and Arg498 in the B.1.1.529 RBD caused additional interactions with hACE2 and the loss of key residues in the B.1.1.529 NTD resulted in decreased interactions with three CDR regions (1-3) in the mAb. Further investigation revealed that B.1.1.529 displayed a stable dynamic that follows a global stability trend. In addition, the dissociation constant (KD), hydrogen bonding analysis, and binding free energy calculations further validated the findings. Hydrogen bonding analysis demonstrated that significant hydrogen bonding reprogramming took place, which revealed key differences in the binding. The total binding free energy using MM/GBSA and MM/PBSA further validated the docking results and demonstrated significant variations in the binding. This study is the first to provide a basis for the higher infectivity of the new SARS-CoV-2 variants and provides a strong impetus for the development of novel drugs against them.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antibodies/chemistry , Antibodies/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/metabolism , Humans , Hydrogen Bonding , Immune Evasion , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding/immunology , Protein Domains/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
5.
World J Gastroenterol ; 27(47): 8199-8200, 2021 Dec 21.
Article in English | MEDLINE | ID: covidwho-1580315

ABSTRACT

In 2016, the World Health Assembly adopted a Global Health Sector Strategy on viral hepatitis, with targets set for the years 2020 and 2030 to achieve hepatitis elimination. The main target of hepatitis elimination strategy is to reduce the incidence of hepatitis B virus (HBV) and hepatitis C virus (HCV) by 90% and mortality by 65% in 2030. In last 5 years, the number of people receiving HCV treatment has increased from 1 million to 9.4 million; however, this number is far from the 2030 target of 40 million people receiving HCV treatment. HBV and HCV incidence rates are down from 1.4 million to 1.1 million annual deaths but this is far from the 2030 target of < 0.5 million deaths. The coronavirus disease 2019 pandemic has severely affected the efforts in the fight against hepatitis. No major donor has committed to investing in the fight against hepatitis. Time is running out. There is a need to speed up efforts in the fight against hepatitis to achieve hepatitis elimination by 2030.


Subject(s)
COVID-19 , Hepatitis B , Hepatitis C , Hepatitis, Viral, Human , Antiviral Agents/therapeutic use , Global Health , Hepacivirus , Hepatitis B/diagnosis , Hepatitis B/drug therapy , Hepatitis B/epidemiology , Hepatitis C/diagnosis , Hepatitis C/drug therapy , Hepatitis C/epidemiology , Hepatitis, Viral, Human/drug therapy , Humans , SARS-CoV-2
6.
Antibiotics (Basel) ; 10(12)2021 Dec 09.
Article in English | MEDLINE | ID: covidwho-1572349

ABSTRACT

(1) Objectives: Patients with COVID-19 infection have been given various formulations and dosages of steroids over the last year and a half. This study aims to compare the effects of different formulations and doses of steroids on the 30 day in-hospital clinical outcome of patients with severe COVID-19 infection. (2) Material and Methods: An analysis of a retrospective cohort was carried out on patients with severe COVID-19 infection in a high-dependency unit (HDU) between February and July 2021. In total, 557 patients were included in this study. Patients who did not receive steroids (124) were excluded. Patients were divided into three groups based on dosages of steroids (Dexamethasone = 6 mg/day, Dexamethasone > 6 mg/day, and Methylprednisolone = 500 mg/day), given for 10 days. First, clinical outcome was evaluated on the 10th day of steroid administration in relation to mode of oxygen delivery. Then, Kaplan-Meier analysis was employed to determine 30 day in-hospital survival in relation to the use of steroid. (3) Results: Three groups were statistically equal according to biochemical characteristics. After 10 days of Methylprednisolone = 500 mg/day vs. Dexamethasone = 6 mg/day, 10.9% vs. 6.2% of patients required invasive ventilation (p = 0.01). The 30 day in-hospital mortality was lowest, 3%, in individuals receiving Dexamethasone = 6 mg/day, compared to 3.9% in individuals receiving Dexamethasone > 6 mg/day and 9.9% in individuals receiving Methylprednisolone = 500 mg/day, respectively. The median elapsed time was longer than 28 days between admission and outcome for Dexamethasone = 6 mg/day, compared to 18 days for Dexamethasone > 6 mg/day and 17 days for Methylprednisolone = 500 mg/day (p = < 0.0001). Dexamethasone = 6 mg/day was found to be a positive predictor of clinical outcome in COVID-19 patients on regression analysis. (4) Conclusions: Low-dose Dexamethasone (6 mg/day) is more effective than high-dose Dexamethasone and Methylprednisolone in improving the survival outcome of severe COVID-19 cases.

7.
Vaccines (Basel) ; 9(11)2021 Nov 15.
Article in English | MEDLINE | ID: covidwho-1538576

ABSTRACT

Yersinia pestis is responsible for plague and major pandemics in Asia and Europe. This bacterium has shown resistance to an array of drugs commonly used for the treatment of plague. Therefore, effective therapeutics measurements, such as designing a vaccine that can effectively and safely prevent Y. pestis infection, are of high interest. To fast-track vaccine development against Yersinia pestis, herein, proteome-wide vaccine target annotation was performed, and structural vaccinology-assisted epitopes were predicted. Among the total 3909 proteins, only 5 (rstB, YPO2385, hmuR, flaA1a, and psaB) were shortlisted as essential vaccine targets. These targets were then subjected to multi-epitope vaccine design using different linkers. EAAK, AAY, and GPGPG as linkers were used to link CTL, HTL, and B-cell epitopes, and an adjuvant (beta defensin) was also added at the N-terminal of the MEVC. Physiochemical characterization, such as determination of the instability index, theoretical pI, half-life, aliphatic index, stability profiling, antigenicity, allergenicity, and hydropathy of the ensemble, showed that the vaccine is highly stable, antigenic, and non-allergenic and produces multiple interactions with immune receptors upon docking. In addition, molecular dynamics simulation confirmed the stable binding and good dynamic properties of the vaccine-TLR complex. Furthermore, in silico and immune simulation of the developed MEVC for Y. pestis showed that the vaccine triggered strong immune response after several doses at different intervals. Neutralization of the antigen was observed at the third day of injection. Conclusively, the vaccine designed here for Y. pestis produces an immune response; however, further immunological testing is needed to unveil its real efficacy.

8.
Antibiotics (Basel) ; 10(11)2021 Nov 13.
Article in English | MEDLINE | ID: covidwho-1512078

ABSTRACT

(1) Background: Severe coronavirus disease can be complicated by a hypercoagulable state in conjunction with sepsis, increasing the risk of venous thromboembolism. This study aimed to observe the effect of anticoagulants on 30-day high-dependency unit (HDU) outcomes of moderate to severe coronavirus disease 2019 (COVID-19) patients of a tertiary care hospital at Rawalpindi, Pakistan. (2) Methods: A retrospective propensity-based case-control study was carried out to examine COVID-19 patients admitted to the HDU. Patient groups who did and did not receive anticoagulants were labeled as "anticoagulant" and "non-anticoagulant", respectively. Case-control matching (1:1) was performed via propensity scores (calculated by a regression model). Kaplan-Meier and logrank analyses were used to study survival probability. Single predictors of outcomes were determined by Cox regression analysis. (3) Results: The anticoagulant group had elevated D-dimers, advanced age, more comorbidities and a higher frequency of severe disease compared to the non-anticoagulant group (p < 0.05). Therefore, 47 cases and 47 matched controls were selected based on their propensity scores. The primary endpoint was outcome (survived vs. died). The 30-day in-HDU mortality was 25.5% for cases and 61.7% for controls (p = 0.0004). The median time from admission to death was 16 days for the case group and 7 days for the control group (p < 0.0001). The 30-day mortality was 19.1% for the enoxaparin group and 16.4% for the heparin group (p > 0.05). Enoxaparin (therapeutic and prophylactic doses) and heparin (prophylactic dose) were found to be independent factors affecting the outcomes of these patients (p < 0.001). (4) Conclusions: Anticoagulants play a beneficial role in reducing mortality among COVID-19 patients. Both anticoagulant formulations, enoxaparin (therapeutic and prophylactic doses) and heparin (prophylactic dose), were associated with improving survival among these patients.

9.
J Mol Model ; 27(7): 206, 2021 Jun 24.
Article in English | MEDLINE | ID: covidwho-1384472

ABSTRACT

The interaction between SARS-CoV-2 Spike protein and angiotensin-converting enzyme 2 (ACE2) is essential to viral attachment and the subsequent fusion process. Interfering with this event represents an attractive avenue for the development of therapeutics and vaccine development. Here, a hybrid approach of ligand- and structure-based virtual screening techniques were employed to disclose similar analogues of a reported antiviral phytochemical, glycyrrhizin, targeting the blockade of ACE2 interaction with the SARS-CoV-2 Spike. A ligand-based similarity search using a stringent cut-off revealed 40 FDA-approved compounds in DrugBank. These filtered hits were screened against ACE2 using a blind docking approach to determine the natural binding tendency of the compounds with ACE2. Three compounds, deslanoside, digitoxin, and digoxin, were reported to show strong binding with ACE2. These compounds bind at the H1-H2 binding pocket, in a manner similar to that of glycyrrhizin which was used as a control. To achieve consistency in the docking results, docking calculations were performed via two sets of docking software that predicted binding energy as ACE2-Deslanoside (AutoDock, -10.3 kcal/mol and DockThor, -9.53 kcal/mol), ACE2-Digitoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.84 kcal/mol), and ACE2-Digoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.81 kcal/mol). The docking results were validated by running molecular simulations in aqueous solution that demonstrated the stability of ACE2 with no major conformational changes in the ligand original binding mode (~ 2 Å average RMSD). Binding interactions remained quite stable with an increased potential for getting stronger as the simulation proceeded. MMGB/PBSA binding free energies were also estimated and these supported the high stability of the complexes compared to the control (~ -50 kcal/mol net MMGB/PBSA binding energy versus ~ -30 kcal/mol). Collectively, the data demonstrated that the compounds shortlisted in this study might be subjected to experimental evaluation to uncover their real blockade capacity of SARS-CoV-2 host ACE2 receptor.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Glycyrrhizic Acid/pharmacology , Receptors, Virus/antagonists & inhibitors , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/chemistry , Animals , Antiviral Agents/chemistry , Binding Sites , COVID-19/enzymology , COVID-19/virology , Drug Discovery , Drug Repositioning , Glycyrrhizic Acid/analogs & derivatives , Glycyrrhizic Acid/chemistry , Host-Pathogen Interactions , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Conformation , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Structure-Activity Relationship
10.
APMIS ; 129(10): 579-586, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1338793

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a novel respiratory disease that has led to a global pandemic and created a havoc. The COVID-19 disease severity varies among individuals, depending on fluctuating symptoms. Many infectious diseases such as hepatitis B and dengue hemorrhagic fever have been associated with ABO blood groups. The aim of this study was to explore whether ABO blood groups might serve as a risk or a protective factor for COVID-19 infection. Moreover, the symptomatic variations of COVID-19 infection among the individuals with different blood groups were also analyzed. An online questionnaire-based survey was conducted in which 305 partakers were included, who had successfully recovered from coronavirus infection. The ABO blood groups of 1294 healthy individuals were also taken as a control. The results of the current study demonstrated that antibody A containing blood groups (blood group B, p-value: 0.049 and blood group O, p-value: 0.289) had a protective role against COVID-19 infection. The comparison of symptomatic variations among COVID-19-infected subjects showed that blood group O subjects had lower chances of experiencing severe symptoms relating to respiratory distress, while subjects with AB blood group were more prone to develop symptoms, but the differences in both groups were found to be statistically non-significant. In conclusion, subjects who do not have anti-A antibodies in their serum (i.e., subjects with group A and AB) are more likely to be infected with COVID-19. The current data showed that there was no significant association of signs and symptoms variations of COVID-19 infection among individuals with different blood groups.


Subject(s)
ABO Blood-Group System , COVID-19/blood , Adolescent , Adult , Age Distribution , COVID-19/epidemiology , COVID-19/prevention & control , Case-Control Studies , Disease Susceptibility , Female , Humans , Male , Middle Aged , Risk Factors , Sex Distribution , Surveys and Questionnaires , Young Adult
11.
Molecules ; 26(5)2021 Mar 07.
Article in English | MEDLINE | ID: covidwho-1136523

ABSTRACT

With the emergence and global spread of the COVID-19 pandemic, the scientific community worldwide has focused on search for new therapeutic strategies against this disease. One such critical approach is targeting proteins such as helicases that regulate most of the SARS-CoV-2 RNA metabolism. The purpose of the current study was to predict a library of phytochemicals derived from diverse plant families with high binding affinity to SARS-CoV-2 helicase (Nsp13) enzyme. High throughput virtual screening of the Medicinal Plant Database for Drug Design (MPD3) database was performed on SARS-CoV-2 helicase using AutoDock Vina. Nilotinib, with a docking value of -9.6 kcal/mol, was chosen as a reference molecule. A compound (PubChem CID: 110143421, ZINC database ID: ZINC257223845, eMolecules: 43290531) was screened as the best binder (binding energy of -10.2 kcal/mol on average) to the enzyme by using repeated docking runs in the screening process. On inspection, the compound was disclosed to show different binding sites of the triangular pockets collectively formed by Rec1A, Rec2A, and 1B domains and a stalk domain at the base. The molecule is often bound to the ATP binding site (referred to as binding site 2) of the helicase enzyme. The compound was further discovered to fulfill drug-likeness and lead-likeness criteria, have good physicochemical and pharmacokinetics properties, and to be non-toxic. Molecular dynamic simulation analysis of the control/lead compound complexes demonstrated the formation of stable complexes with good intermolecular binding affinity. Lastly, affirmation of the docking simulation studies was accomplished by estimating the binding free energy by MMPB/GBSA technique. Taken together, these findings present further in silco investigation of plant-derived lead compounds to effectively address COVID-19.


Subject(s)
Methyltransferases/antagonists & inhibitors , Methyltransferases/metabolism , RNA Helicases/antagonists & inhibitors , RNA Helicases/metabolism , SARS-CoV-2/enzymology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Binding Sites , Biological Availability , COVID-19/drug therapy , Computational Biology/methods , Databases, Chemical , Drug Design , Humans , Hydrogen Bonding , Methyltransferases/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Phytochemicals/chemistry , Phytochemicals/metabolism , Plants, Medicinal/chemistry , Protein Binding , Protein Domains/drug effects , Pyrimidines/chemistry , Pyrimidines/metabolism , Pyrimidines/pharmacokinetics , Pyrimidines/toxicity , RNA Helicases/chemistry , Structure-Activity Relationship , Thermodynamics , Viral Nonstructural Proteins/chemistry
12.
J Mol Liq ; 330: 115636, 2021 May 15.
Article in English | MEDLINE | ID: covidwho-1093177

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a novel coronavirus and the etiological agent of global pandemic coronavirus disease (COVID-19) requires quick development of potential therapeutic strategies. Computer aided drug design approaches are highly efficient in identifying promising drug candidates among an available pool of biological active antivirals with safe pharmacokinetics. The main protease (MPro) enzyme of SARS-CoV-2 is considered key in virus production and its crystal structures are available at excellent resolution. This marks the enzyme as a good starting receptor to conduct an extensive structure-based virtual screening (SBVS) of ASINEX antiviral library for the purpose of uncovering valuable hits against SARS-CoV-2 MPro. A compound hit (BBB_26580140) was stand out in the screening process, as opposed to the control, as a potential inhibitor of SARS-CoV-2 MPro based on a combined approach of SBVS, drug likeness and lead likeness annotations, pharmacokinetics, molecular dynamics (MD) simulations, and end point MM-PBSA binding free energy methods. The lead was further used in ligand-based similarity search (LBSS) that found 33 similar compounds from the ChEMBL database. A set of three compounds (SCHEMBL12616233, SCHEMBL18616095, and SCHEMBL20148701), based on their binding affinity for MPro, was selected and analyzed using extensive MD simulation, hydrogen bond profiling, MM-PBSA, and WaterSwap binding free energy techniques. The compounds conformation with MPro show good stability after initial within active cavity moves, a rich intermolecular network of chemical interactions, and reliable relative and absolute binding free energies. Findings of the study suggested the use of BBB_26580140 lead and its similar analogs to be explored in vivo which might pave the path for rational drug discovery against SARS-CoV-2 MPro.

13.
J Immunol Res ; 2020: 8893483, 2020.
Article in English | MEDLINE | ID: covidwho-939929

ABSTRACT

The global health crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19, has resulted in a negative impact on human health and on social and economic activities worldwide. Researchers around the globe need to design and develop successful therapeutics as well as vaccines against the novel COVID-19 disease. In the present study, we conducted comprehensive computer-assisted analysis on the spike glycoprotein of SARS-CoV-2 in order to design a safe and potent multiepitope vaccine. In silico epitope prioritization shortlisted six HLA I epitopes and six B-cell-derived HLA II epitopes. These high-ranked epitopes were all connected to each other via flexible GPGPG linkers, and at the N-terminus side, the sequence of Cholera Toxin ß subunit was attached via an EAAAK linker. Structural modeling of the vaccine was performed, and molecular docking analysis strongly suggested a positive association of a multiepitope vaccine with Toll-like Receptor 3. The structural investigations of the vaccine-TLR3 complex revealed the formation of fifteen interchain hydrogen bonds, thus validating its integrity and stability. Moreover, it was found that this interaction was thermodynamically feasible. In conclusion, our data supports the proposition that a multiepitope vaccine will provide protective immunity against COVID-19. However, further in vivo and in vitro experiments are needed to validate the immunogenicity and safety of the candidate vaccine.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Amino Acid Sequence , COVID-19/epidemiology , COVID-19/prevention & control , Computational Biology , Computer Simulation , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/chemistry , Humans , Hydrogen Bonding , Immunogenicity, Vaccine , Molecular Docking Simulation , Pandemics/prevention & control , Spike Glycoprotein, Coronavirus/chemistry , Static Electricity , Thermodynamics , Vaccines, Subunit/immunology
14.
J Mol Liq ; 324: 114734, 2021 Feb 15.
Article in English | MEDLINE | ID: covidwho-917385

ABSTRACT

The nucleocapsid (N) protein of SARS-COV-2, a virus responsible for the current COVID-19 pandemic, is considered a potential candidate for the design of new drugs and vaccines. The protein is central to several critical events in virus production, with its highly druggable nature and rich antigenic determinants making it an excellent anti-viral biomolecule. Docking-based virtual screening using the Asinex anti-viral library identified binding of drug molecules at three specific positions: loop 1 region, loop 2 region and ß-sheet core pockets, the loop 2 region being the most common binding and stable site for the bulk of the molecules. In parallel, the protein was characterized by vaccine design perspective and harboured three potential B cell-derived T cell epitopes: PINTNSSPD, GVPINTNSS, and DHIGTRNPA. The epitopes are highly antigenic, virulent, non-allergic, non-toxic, bind with good affinity to the highly prevalent DRB*0101 allele and show an average population coverage of 95.04%. A multi-epitope vaccine ensemble which was 83 amino acids long was created. This was highly immunogenic, robust in generating both humoral and cellular immune responses, thermally stable, and had good physicochemical properties that could be easily analyzed in in vivo and in vitro studies. Conformational dynamics of both drug and vaccine ensemble with respect to the receptors are energetically stable, shedding light on favourable conformation and chemical interactions. These facts were validated by subjecting the complexes to relative and absolute binding free energy methods of MMGB/PBSA and WaterSwap. A strong agreement on the system stability was disclosed that supported ligand high affinity potential for the receptors. Collectively, this work sought to provide preliminary experimental data of existing anti-viral drugs as a possible therapy for COVID-19 infections and a new peptide-based vaccine for protection against this pandemic virus.

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