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1.
Webology ; 19(2):8957-8980, 2022.
Article in English | ProQuest Central | ID: covidwho-1958091

ABSTRACT

COVID-19 pandemic has emerged as a global health emergency. It poses a serious challenge to healthcare professionals since they provide healthcare facilities to affected population in extremely stressful circumstances, which may affect their psychological wellbeing. Keeping this in mind, this study was conducted to understand the psychological impact of COVID-19 pandemic on healthcare professionals. Following PRISMA protocol, all research papers published between January 2020 and May 2020 were searched in databases like, e.g., Pub-Med, Science Direct and Google-Scholar databases. After screening through proper inclusion criteria, only 26 studies were finally selected for detailed analysis. Results revealed that healthcare professionals suffered from a variety of psychological disorders, particularly from depression, anxiety, and sleep problems. There were also different predisposing factors that have increased the risk of such adverse psychological symptoms among healthcare professionals. And to deal with such symptoms, the healthcare professionals had adopted different coping strategies. The review concludes that COVID-19 pandemic has a severe impact on the psychological well-being of healthcare professionals, therefore, a broad range of interventions are required for mitigating adverse psychological impact of COVID-19 pandemic among healthcare professionals.

2.
J Mol Struct ; 1265: 133391, 2022 Oct 05.
Article in English | MEDLINE | ID: covidwho-1867596

ABSTRACT

In the fall of 2019, a new type of coronavirus took place in Wuhan city, China, and rapidly spread across the world and urges the scientific community to develop antiviral therapeutic agents. In our effort we have synthesized a new hydrazide derivative, (E)-N'-(1-(4-bromophenyl)ethylidene)-2-(6-methoxynaphthalen-2-yl)propanehydrazide for this purpose because of its potential inhibitory proprieties. The asymmetric unit of the title molecule consists of two independent molecules differing noticeably in conformation. In the crystal, the independent molecules are linked by N-H···O and C-H···O hydrogen bonds and C-H···π(ring) interactions into helical chains extending along the b-axis direction. The chains are further joined by additional C-H···π(ring) interactions into the full 3-D structure. To obtain a structure-activity relationship, the DFT-NBO analysis is performed to study the intrinsic electronic properties of the title compound. Molecular modeling studies were also conducted to examine the binding affinity of the compound for the SARS-CoV-2 main protease enzyme and to determine intermolecular binding interactions. The compound revealed a stable binding mode at the enzyme active pocket with a binding energy value of -8.1 kcal/mol. Further, stable dynamics were revealed for the enzyme-compound complex and reported highly favorable binding energies. The net MMGBSA binding energy of the complex is -37.41 kcal/mol while the net MMPBSA binding energy is -40.5 kcal/mol. Overall, the compound disclosed the strongest bond of ing the main protease enzyme and might be a good lead for further structural optimization.

3.
Ther Adv Vaccines Immunother ; 10: 25151355221080724, 2022.
Article in English | MEDLINE | ID: covidwho-1799130

ABSTRACT

Background: Health care workers (HCWs) are exposed to high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to close contact with infected patients in hospital. The objective of this study was to estimate the seroprevalence and to identify the exposure risk of various subgroups among HCWs to prioritize them for early vaccination. Methods: This was a multicentre cross-sectional study conducted between 15 and 29 June 2020. A total of 987 HCWs were recruited randomly from two major tertiary-care hospitals of Peshawar city, Pakistan. The HCWs included doctors, nurses, paramedics and hospital support staff. The US Food and Drug Administration (FDA)-approved kit was used for the detection of SARS-CoV-2 antibodies. Results: Overall, 310 (31.4%) HCWs were seropositive for SARS-CoV-2 antibodies (95% confidence interval, CI: 28.5-34.4). Seroprevalence was higher in males (33.5%) and in age group 51-60 years (40.9%). Seropositivity increased with increasing age from 8.3% in age group ⩽20 to 40.9% in 51-60 years of age group (p < 0.05). The highest seroprevalence was identified in paramedical staff (42·5%, 95% CI: 36.6-48.6) followed by nursing staff (38·8%, 95% CI: 32.1-45.7). In logistic regression, being a male HCW led to higher risk of seropositivity (odds ratio, OR: 1.50, 95% CI: 1·06-2.13. p < 0.05) compared with female staff members. The odds of seropositivity was higher in nurses (OR: 3·47, 95% CI: 1.99-6.05. p < 0.01), paramedical staff (OR: 3·19, 95% CI: 1.93-5.28. p < 0.01) and hospital support staff (OR: 2·47, 95% CI: 1.29-4.7. p < 0.01) compared with consultants. Conclusion: Overall, our results concluded that nursing and paramedical staff are at higher risk and should be vaccinated on priority.

4.
Ir J Med Sci ; 2022 Apr 12.
Article in English | MEDLINE | ID: covidwho-1782942

ABSTRACT

BACKGROUND : Since the pandemic of SARS-CoV-2 began, our understanding of the pathogenesis and immune responses to this virus has continued to evolve. It has been shown that this infection produces natural detectable immune responses in many cases. However, the duration and durability of immunity and its effect on the severity of the illness are still under investigation. Moreover, the protective effects of antibodies against new SARS-CoV-2 variants still remain unclear. OBJECTIVES: To assess the incidence and associated demographic features of SARS-CoV-2 infection in anti-nucleocapsid IgG-positive and anti-nucleocapsid IgG-negative healthcare workers. MATERIAL AND METHODS: This prospective longitudinal cohort study was conducted in Peshawar Medical College group of hospitals of Prime Foundation. Anti-nucleocapsid IgG sero-positive and anti-nucleocapsid IgG sero-negative healthcare workers were followed for a period of 6 months (from 1 Aug 2020 to 31 Jan 2021), and the incidence of SARS-CoV-2 was confirmed by RT-PCR. RESULTS: A total number of 555 cohorts were followed for a period of 6 months; of them 365 (65.7%) were anti-nucleocapsid-negative (group A) and 190 (34.3%) were anti-nucleocapsid-positive (group B) healthcare workers. The mean age of the study cohort was 33.85 ± 9.80 (anti-N (-), 34.2 ± 10.58; anti-N ( +), 33.5 ± 9.50). The median antibody level in anti-nucleocapsid-positive HCWs was 15.95 (IQR: 5.24-53.4). Male gender was the majority in both groups (group A, 246 (67%), group B, 143 (48%)) with statistically significant difference (P < 0.05). Majority of the HCWs were blood group B in both groups (34% each). None of the 190 anti-nucleocapsid-positive HCWs developed subsequent SARS-CoV-2 re-infection, while 17% (n = 65) HCWs developed infection in anti-nucleocapsid-negative group during the 6-month follow-up period. CONCLUSION: In conclusion, none of the anti-nucleocapsid-positive HCWs developed SARS-CoV-2 re-infection in this study, and the presence of IgG anti-nucleocapsid antibodies substantially reduce the risk of re-infection for a period of 6 months.

5.
Therapeutic advances in vaccines and immunotherapy ; 10, 2022.
Article in English | EuropePMC | ID: covidwho-1738172

ABSTRACT

Background: Health care workers (HCWs) are exposed to high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to close contact with infected patients in hospital. The objective of this study was to estimate the seroprevalence and to identify the exposure risk of various subgroups among HCWs to prioritize them for early vaccination. Methods: This was a multicentre cross-sectional study conducted between 15 and 29 June 2020. A total of 987 HCWs were recruited randomly from two major tertiary-care hospitals of Peshawar city, Pakistan. The HCWs included doctors, nurses, paramedics and hospital support staff. The US Food and Drug Administration (FDA)–approved kit was used for the detection of SARS-CoV-2 antibodies. Results: Overall, 310 (31.4%) HCWs were seropositive for SARS-CoV-2 antibodies (95% confidence interval, CI: 28.5–34.4). Seroprevalence was higher in males (33.5%) and in age group 51–60 years (40.9%). Seropositivity increased with increasing age from 8.3% in age group ⩽20 to 40.9% in 51–60 years of age group (p < 0.05). The highest seroprevalence was identified in paramedical staff (42·5%, 95% CI: 36.6–48.6) followed by nursing staff (38·8%, 95% CI: 32.1–45.7). In logistic regression, being a male HCW led to higher risk of seropositivity (odds ratio, OR: 1.50, 95% CI: 1·06–2.13. p < 0.05) compared with female staff members. The odds of seropositivity was higher in nurses (OR: 3·47, 95% CI: 1.99–6.05. p < 0.01), paramedical staff (OR: 3·19, 95% CI: 1.93–5.28. p < 0.01) and hospital support staff (OR: 2·47, 95% CI: 1.29–4.7. p < 0.01) compared with consultants. Conclusion: Overall, our results concluded that nursing and paramedical staff are at higher risk and should be vaccinated on priority.

6.
JAMA Oncol ; 8(3): 420-444, 2022 Mar 01.
Article in English | MEDLINE | ID: covidwho-1664325

ABSTRACT

IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.


Subject(s)
Global Burden of Disease , Neoplasms , 50308 , Global Health , Humans , Incidence , Neoplasms/epidemiology , Prevalence , Quality-Adjusted Life Years , Risk Factors
8.
Molecules ; 27(2)2022 Jan 16.
Article in English | MEDLINE | ID: covidwho-1628349

ABSTRACT

Hendra virus (HeV) belongs to the paramyxoviridae family of viruses which is associated with the respiratory distress, neurological illness, and potential fatality of the affected individuals. So far, no competitive approved therapeutic substance is available for HeV. For that reason, the current research work was conducted to propose some novel compounds, by adopting a Computer Aided Drug Discovery approach, which could be used to combat HeV. The G attachment Glycoprotein (Ggp) of HeV was selected to achieve the primary objective of this study, as this protein makes the entry of HeV possible in the host cells. Briefly, a library of 6000 antiviral compounds was screened for potential drug-like properties, followed by the molecular docking of short-listed compounds with the Protein Data Bank (PDB) structure of Ggp. Docked complexes of top two hits, having maximum binding affinities with the active sites of Ggp, were further considered for molecular dynamic simulations of 200 ns to elucidate the results of molecular docking analysis. MD simulations and Molecular Mechanics Energies combined with the Generalized Born and Surface Area (MMGBSA) or Poisson-Boltzmann and Surface Area (MMPBSA) revealed that both docked complexes are stable in nature. Furthermore, the same methodology was used between lead compounds and HeV Ggp in complex with its functional receptor in human, Ephrin-B2. Surprisingly, no major differences were found in the results, which demonstrates that our identified compounds can also perform their action even when the Ggp is attached to the Ephrin-B2 ligand. Therefore, in light of all of these results, we strongly suggest that compounds (S)-5-(benzylcarbamoyl)-1-(2-(4-methyl-2-phenylpiperazin-1-yl)-2-oxoethyl)-6-oxo-3,6-dihydropyridin-1-ium-3-ide and 5-(cyclohexylcarbamoyl)-1-(2-((2-(3-fluorophenyl)-2-methylpropyl)amino)-2-oxoethyl)-6-oxo-3,6-dihydropyridin-1-ium-3-ide could be considered as potential therapeutic agents against HeV; however, further in vitro and in vivo experiments are required to validate this study.


Subject(s)
Antiviral Agents/chemistry , Computational Chemistry/methods , Viral Fusion Proteins/chemistry , Antiviral Agents/metabolism , Ephrin-B2/chemistry , Ephrin-B2/metabolism , Hendra Virus/drug effects , Humans , Hydrogen Bonding , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Receptors, Virus/chemistry , Receptors, Virus/metabolism , Small Molecule Libraries , Viral Fusion Proteins/antagonists & inhibitors , Viral Fusion Proteins/metabolism , Water/chemistry
9.
Comput Biol Med ; 141: 105163, 2022 02.
Article in English | MEDLINE | ID: covidwho-1588032

ABSTRACT

The spike protein of SARS-CoV-2 and the host ACE2 receptor plays a vital role in the entry to the cell. Among which the hotspot residue 501 is continuously subjected to positive selection pressure and induces unusual virulence. Keeping in view the importance of the hot spot residue 501, we predicted the potentially emerging structural variants of 501 residue. We analyzed the binding pattern of wild type and mutants (Spike RBD) to the ACE2 receptor by deciphering variations in the amino acids' interaction networks by graph kernels along with evolutionary, network metrics, and energetic information. Our analysis revealed that N501I, N501T, and N501V increase the binding affinity and alter the intra and inter-residue bonding networks. The N501T has shown strong positive selection and fitness in other animals. Docking results and repeated simulations (three times) confirmed the structural stability and tighter binding of these three variants, correlated with the previous results following the global stability trend. Consequently, we reported three variants N501I, N501T, and N501V could worsen the situation further if they emerged. The relations between the viral fitness and binding affinity is a complicated game thus the emergence of high affinity mutations in the SARS-CoV-2 RBD brings up the question of whether or not positive selection favours these mutations or not?


Subject(s)
SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2 , Animals , COVID-19/virology , Humans , Molecular Dynamics Simulation , Mutation , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/genetics
10.
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.

11.
Microorganisms ; 9(11)2021 Nov 11.
Article in English | MEDLINE | ID: covidwho-1512502

ABSTRACT

Glucose-regulated protein 78 (GRP78) might be a receptor for SARS-CoV-2 to bind and enter the host cell. Recently reported mutations in the spike glycoprotein unique to the receptor-binding domain (RBD) of different variants might increase the binding and pathogenesis. However, it is still not known how these mutations affect the binding of RBD to GRP78. The current study provides a structural basis for the binding of GRP78 to the different variants, i.e., B.1.1.7, B.1.351, B.1.617, and P.1 (spike RBD), of SARS-CoV-2 using a biomolecular simulation approach. Docking results showed that the new variants bound stronger than the wild-type, which was further confirmed through the free energy calculation results. All-atom simulation confirmed structural stability, which was consistent with previous results by following the global stability trend. We concluded that the increased binding affinity of the B.1.1.7, B.1.351, and P.1 variants was due to a variation in the bonding network that helped the virus induce a higher infectivity and disease severity. Consequently, we reported that the aforementioned new variants use GRP78 as an alternate receptor to enhance their seriousness.

12.
Comput Biol Med ; 138: 104936, 2021 11.
Article in English | MEDLINE | ID: covidwho-1458824

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Reports of new variants that potentially increase virulence and viral transmission, as well as reduce the efficacy of available vaccines, have recently emerged. In this study, we computationally analyzed the N439K, S477 N, and T478K variants for their ability to bind Angiotensin-converting enzyme 2 (ACE2). We used the protein-protein docking approach to explore whether the three variants displayed a higher binding affinity to the ACE2 receptor than the wild type. We found that these variants alter the hydrogen bonding network and the cluster of interactions. Additional salt bridges, hydrogen bonds, and a high number of non-bonded contacts (i.e., non-bonded interactions between atoms in the same molecule and those in other molecules) were observed only in the mutant complexes, allowing efficient binding to the ACE2 receptor. Furthermore, we used a 2.0-µs all-atoms simulation approach to detect differences in the structural dynamic features of the resulting protein complexes. Our findings revealed that the mutant complexes possessed stable dynamics, consistent with the global trend of mutations yielding variants with improved stability and enhanced affinity. Binding energy calculations based on molecular mechanics/generalized Born surface area (MM/GBSA) further revealed that electrostatic interactions principally increased net binding energies. The stability and binding energies of N439K, S477 N, and T478K variants were enhanced compared to the wild-type-ACE2 complex. The net binding energy of the systems was -31.86 kcal/mol for the wild-type-ACE2 complex, -67.85 kcal/mol for N439K, -69.82 kcal/mol for S477 N, and -69.64 kcal/mol for T478K. The current study provides a basis for exploring the enhanced binding abilities and structural features of SARS-CoV-2 variants to design novel therapeutics against the virus.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19 , Spike Glycoprotein, Coronavirus , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Computational Biology , Humans , Molecular Dynamics Simulation , Protein Binding , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
13.
Comput Biol Med ; 133: 104420, 2021 06.
Article in English | MEDLINE | ID: covidwho-1385348

ABSTRACT

Reports of the novel and more contagious strains of SARS-CoV-2 originating in different countries have further aggravated the pandemic situation. The recent substitutions in spike protein may be critical for the virus to evade the host's immune system and therapeutics that have already been developed. Thus, this study has employed an immunoinformatics pipeline to target the spike protein of this novel strain to construct an immunogenic epitope (CTL, HTL, and B cell) vaccine against the new variant. Our investigation revealed that 12 different epitopes imparted a critical role in immune response induction. This was validated by an exploration of physiochemical properties and experimental feasibility. In silico and host immune simulation confirmed the expression and induction of both primary and secondary immune factors such as IL, cytokines, and antibodies. The current study warrants further lab experiments to demonstrate its efficacy and safety.


Subject(s)
COVID-19 , Viral Vaccines , Cloning, Molecular , Computer Simulation , Epitopes, B-Lymphocyte , Epitopes, T-Lymphocyte , Humans , Immunity , Molecular Docking Simulation , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Vaccines, Subunit
14.
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
15.
Comput Biol Med ; 141: 104714, 2022 02.
Article in English | MEDLINE | ID: covidwho-1330721

ABSTRACT

The evolution of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants around the globe has made the coronavirus disease 2019 (COVID-19) pandemic more worrisome, pressuring the health care system and resulting in an increased mortality rate. Recent studies recognized neuropilin-1 (NRP1) as a key facilitator in the invasion of the new SARS-CoV-2 into the host cell. Therefore, it is considered an imperative drug target for the treatment of COVID-19. Hence, a thorough analysis was needed to understand the impact and to guide new therapeutics development. In this study, we used structural and biomolecular simulation techniques to identify novel marine natural products which could block this receptor and stop the virus entry. We discovered that the binding affinity of CMNPD10175, CMNPD10017, CMNPD10114, CMNPD10115, CMNPD10020. CMNPD10018, CMNPD10153, CMNPD10149 CMNPD10464 and CMNPD10019 were substantial during the virtual screening (VS). We further explored these compounds by analyzing their absorption, distribution, metabolism, and excretion and toxicity (ADMET) properties and structural-dynamics features. Free energy calculations further established that all the compounds exhibit stronger binding energy for NRP1. Consequently, we hypothesized that these compounds might be the best lead candidates for therapeutic interventions hindering virus binding to the host cell. This study provides a strong impetus to develop novel drugs against the SARS-CoV-2 by targeting NRP1.


Subject(s)
Biological Products/pharmacology , Neuropilin-1/metabolism , SARS-CoV-2 , Virus Internalization , COVID-19 , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , SARS-CoV-2/drug effects
16.
Appl Biochem Biotechnol ; 193(11): 3602-3623, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1330411

ABSTRACT

The novel coronavirus disease that arises in the end of 2019 (COVID-19) in Wuhan, China, has rapidly spread over the globe and was considered as a world pandemic. Currently, various antiviral therapies or vaccines are available, and many researches are ongoing for further treatments. Targeting the coronavirus' main protease (key enzyme: 3CLpro) is growing in importance in anti-SARS-CoV-2 drug discovery process. The present study aims at predicting the antiviral activity of two novel compounds using in silico approaches that might become potential leads against SARS-CoV-2. The 3D structures of the new compounds are elucidated by single-crystal X-ray techniques. The interactions between different units of 4 and 5 were emphasized by analyzing their corresponding Hirshfeld surfaces and ESP plots. NBO and FMO analyses were investigated as well. Molecular docking combined with molecular dynamics simulations (MDs) was performed to investigate the binding modes and molecular interactions of 4 and 5 with the amino acids of coronavirus main protease (6LU7) protein. The best docking scores were obtained for both ligands through the major binding interactions via hydrogen/hydrophobic bonds with the key amino acids in the active site: HIS41, CYS145, MET49, MET165, HIS172, and GLU166 amino acids. A MD simulation study was also performed for 100 ns to validate the stability behavior of the main protease 3CLpro-ligand complexes. The MD simulation study successfully confirmed the stability of the ligands in the binding site as potent anti-SARS-CoV-2 (COVID-19) inhibitors. Additionally, MMPBSA energy of both docked complexes was determined as a validation assay of docking and MD simulations to validate compound conformation and interaction stability with 3CLpro. The synthesized compounds might be helpful in the fight against COVID-19 prior to biological activity confirmation in vitro and in vivo.


Subject(s)
Antiviral Agents/chemistry , COVID-19/virology , Coronavirus 3C Proteases/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Antiviral Agents/chemical synthesis , Binding Sites , Catalytic Domain , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/metabolism , Drug Discovery , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/chemical synthesis , SARS-CoV-2/chemistry
17.
J Biomol Struct Dyn ; 39(12): 4225-4233, 2021 08.
Article in English | MEDLINE | ID: covidwho-1317833

ABSTRACT

Nigella sativa or black seed is used as a medicinal plant around the globe. Oil and seeds have a long tradition of folklore use in various medicinal and food systems. The conventional therapeutic use of Nigella sativa, in different ways, has been reported in several studies to treat different diseases including influenza, headache, hypertension, diabetes, inflammation, eczema, fever, cough, asthma, bronchitis, and fever. Based on previously reported potential therapeutic uses of N. sativa compounds, and keeping in mind the dire need of time for the development of potent antiviral, a combined docking, ADMET properties calculation, molecular dynamics, and MM-PBSA approaches were applied in the current study to check the therapeutic potentials of N. sativa chief constituents against COVID-19. Among the studied compounds, we found that dithymoquinone (DTQ), with binding affinity of -8.6 kcal/mol compared to a positive control (chloroquine, -7.2 kcal/mol) , has the high potential of binding at SARS-CoV-2:ACE2 interface and thus could be predicted as a plausible inhibitor to disrupt viral-host interactions. Molecular dynamics simulation of 100 ns well complemented binding affinity of the compound and revealed strong stability of DTQ at the docked site. Additionally, MM-PBSA also affirms the docking results. Compound DTQ of the present study, if validated in wet lab experiments, could be used to treat COVID-19 and could serve as a lead in the future for development of more effective natural antivirals against COVID-19. Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Nigella sativa , Adipates , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans , Molecular Docking Simulation , SARS-CoV-2 , Succinates
18.
Chembiochem ; 22(16): 2641-2649, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1279349

ABSTRACT

The evolution of new SARS-CoV-2 variants around the globe has made the COVID-19 pandemic more worrisome, further pressuring the health care system and immunity. Novel variations that are unique to the receptor-binding motif (RBM) of the receptor-binding domain (RBD) spike glycoprotein, i. e. L452R-E484Q, may play a different role in the B.1.617 (also known as G/452R.V3) variant's pathogenicity and better survival compared to the wild type. Therefore, a thorough analysis is needed to understand the impact of these mutations on binding with host receptor (RBD) and to guide new therapeutics development. In this study, we used structural and biomolecular simulation techniques to explore the impact of specific mutations (L452R-E484Q) in the B.1.617 variant on the binding of RBD to the host receptor ACE2. Our analysis revealed that the B.1.617 variant possesses different dynamic behaviours by altering dynamic-stability, residual flexibility and structural compactness. Moreover, the new variant had altered the bonding network and structural-dynamics properties significantly. MM/GBSA technique was used, which further established the binding differences between the wild type and B.1.617 variant. In conclusion, this study provides a strong impetus to develop novel drugs against the new SARS-CoV-2 variants.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Humans , Molecular Docking Simulation , Protein Binding , Protein Domains , Virulence
19.
Bioinform Biol Insights ; 15: 11779322211021430, 2021.
Article in English | MEDLINE | ID: covidwho-1262480

ABSTRACT

BACKGROUND: A recent COVID-19 pandemic has resulted in a large death toll rate globally and even no cure or vaccine has been successfully employed to combat this disease. Patients have been reported with multi-organ dysfunction along with acute respiratory distress syndrome which implies a critical situation for patients and made them difficult to breathe and survive. Moreover, pathology of COVID-19 is also related to cytokine storm which indicates the elevated levels of interleukin (IL)-1, IL-6, IL-12, and IL-18 along with tumor necrosis factor (TNF)-α. Among them, the proinflammatory cytokine IL-6 has been reported to be induced via binding of severe acute respiratory syndrome coronavirus 2 (SARS)-CoV-2 to the host receptors. METHODOLOGY: Interleukin-6 blockade has been proposed to constitute novel therapeutics against COVID-19. Thus, in this study, 15 phytocompounds with known antiviral activity have been subjected to test for their inhibitory effect on IL-6. Based on the affinity prediction, top 3 compounds (isoorientin, lupeol, and andrographolide) with best scores were selected for 50 ns molecular dynamics simulation and MMGB/PBSA binding free energy analysis. RESULTS: Three phytocompounds including isoorientin, lupeol, and andrographolide have shown strong interactions with the targeted protein IL-6 with least binding energies (-7.1 to -7.7 kcal/mol). Drug-likeness and ADMET profiles of prioritized phytocompounds are also very prominsing and can be further tested to be potential IL-6 blockers and thus benficial for COVID-19 treatment. The moelcular dynamics simulation couple with MMGB/PBSA binding free energy estimation validated conformational stability of the ligands and stronger intermolecular binding. The mean RMSD of the complexes is as: IL6-isoorientin complex (3.97 Å ± 0.77), IL6-lupeol (3.97 Å ± 0.76), and IL6-andrographolide complex (3.96 Å ± 0.77). In addition, the stability observation was affirmed by compounds mean RMSD: isoorientin (0.72 Å ± 0.32), lupeol (mean 0.38 Å ± 0.08), and andrographolide (1.09 Å ± 0.49). A similar strong agreement on systems stability was unraveled by MMGB/PBSA that found net binding net ~ -20 kcal/mol for the complexes dominated by van der Waal interaction energy. CONCLUSION: It has been predicted that proposing potential IL-6 inhibitors with less side effects can help critical COVID-19 patients because it may control the cytokine storm, a major responsible factor of its pathogenesis. In this study, 3 potential phytocompounds have been proposed to have inhibitory effect on IL-6 that can be tested as potential therapeutic options against SARS-CoV-2.

20.
Infection ; 49(5): 983-988, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1241719

ABSTRACT

PURPOSE: Seroprevalence surveys from different countries have reported SARS CoV-2 antibodies below 20% even in the most adversely affected areas and herd immunity cannot be predicted till more than half of the population gets the disease. The purpose of this survey was to estimate the magnitude of community-based spread of the infection, associated immunity, and the future prospects and proximity to a 'herd community'. METHODS: The study was undertaken as a cluster randomized, cross-sectional countrywide survey. This largest community-based seroprevalence data of SARS-CoV-2 were collected between 15th and 31st July, 2020 from seven randomly selected cities belonging to the three most populous provinces of Pakistan. The FDA approved kit of ROCHE was used for detection of SARS-CoV-2 antibodies. RESULTS: Serum samples of 15,390 participants were tested for SARS CoV-2 antibodies with an overall seroprevalence of 42.4%. The seroprevalence ranged from 31.1% to 48.1% in different cities with the highest in Punjab province (44.5%). In univariable analysis, the odds of seropositivity was higher in men compared to women (OR: 1.10, 95% CI: 1.01-1.19, P < 0.05). In multivariable analysis, the risk of being seropositive was lower (OR 0.72, 95% CI: 0.60-0.87, P < 0.01) in younger group (≤ 20 years) than in those aged above 60 years. CONCLUSION: The study concluded that despite a reasonable seroprevalence, the country is yet to reach the base minimum of estimations for herd immunity. The durability of immunity though debated at the moment, has shown an evidenced informed shift towards longer side.


Subject(s)
COVID-19 , SARS-CoV-2 , Aged , Antibodies, Viral , Cross-Sectional Studies , Female , Humans , Immunity, Herd , Male , Pakistan/epidemiology , Seroepidemiologic Studies
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