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1.
Front Med (Lausanne) ; 9: 825245, 2022.
Article in English | MEDLINE | ID: covidwho-1862616

ABSTRACT

The emergence of several novel SARS-CoV-2 variants regarded as variants of concern (VOCs) has exacerbated pathogenic and immunologic prominences, as well as reduced diagnostic sensitivity due to phenotype modification-capable mutations. Furthermore, latent and more virulent strains that have arisen as a result of unique mutations with increased evolutionary potential represent a threat to vaccine effectiveness in terms of incoming and existing variants. As a result, resisting natural immunity, which leads to higher reinfection rates, and avoiding vaccination-induced immunization, which leads to a lack of vaccine effectiveness, has become a crucial problem for public health around the world. This study attempts to review the genomic variation and pandemic impact of emerging variations of concern based on clinical characteristics management and immunization effectiveness. The goal of this study is to gain a better understanding of the link between genome level polymorphism, clinical symptom manifestation, and current vaccination in the instance of VOCs.

2.
Front Mol Biosci ; 8: 791642, 2021.
Article in English | MEDLINE | ID: covidwho-1708566

ABSTRACT

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic due to the high transmission and mortality rate of this virus. The world health and economic sectors have been severely affected by this deadly virus, exacerbated by the lack of sufficient efficient vaccines. The design of effective drug candidates and their rapid development is necessary to combat this virus. In this study, we selected 23 antimicrobial peptides from the literature and predicted their structure using PEP-FOLD 3.5. In addition, we docked them to the SARS-CoV-2 spike protein receptor-binding domain (RBD) to study their capability to inhibit the RBD, which plays a significant role in virus binding, fusion and entry into the host cell. We used several docking programs including HDOCK, HPEPDOCK, ClusPro, and HawkDock to calculate the binding energy of the protein-peptide complexes. We identified four peptides with high binding free energy and docking scores. The docking results were further verified by molecular dynamics (MD) simulations to characterize the protein-peptide complexes in terms of their root-mean-square fluctuation (RMSF), root-mean-square deviation (RMSD), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond formation. Allergenicity and toxicity predictions suggested that the peptides we identified were non-allergenic and non-toxic. This study suggests that these four antimicrobial peptides could inhibit the RBD of SARS-CoV-2. Future in vitro and in vivo studies are necessary to confirm this.

3.
Molecules ; 26(22)2021 Nov 20.
Article in English | MEDLINE | ID: covidwho-1524087

ABSTRACT

A series of methyl ß-D-galactopyranoside (MGP, 1) analogs were selectively acylated with cinnamoyl chloride in anhydrous N,N-dimethylformamide/triethylamine to yield 6-O-substitution products, which was subsequently converted into 2,3,4-tri-O-acyl analogs with different acyl halides. Analysis of the physicochemical, elemental, and spectroscopic data of these analogs revealed their chemical structures. In vitro antimicrobial testing against five bacteria and two fungi and the prediction of activity spectra for substances (PASS) showed promising antifungal functionality comparing to their antibacterial activities. Minimum inhibition concentration (MIC) and minimum bactericidal concentration (MBC) tests were conducted for four compounds (4, 5, 6, and 9) based on their activity. MTT assay showed low antiproliferative activity of compound 9 against Ehrlich's ascites carcinoma (EAC) cells with an IC50 value of 2961.06 µg/mL. Density functional theory (DFT) was used to calculate the thermodynamic and physicochemical properties whereas molecular docking identified potential inhibitors of the SARS-CoV-2 main protease (6Y84). A 150-ns molecular dynamics simulation study revealed the stable conformation and binding patterns in a stimulating environment. In-silico ADMET study suggested all the designed molecules to be non-carcinogenic, with low aquatic and non-aquatic toxicity. In summary, all these antimicrobial, anticancer and in silico studies revealed that newly synthesized MGP analogs possess promising antiviral activity, to serve as a therapeutic target for COVID-19.


Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Galactose/analogs & derivatives , Animals , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacokinetics , Antifungal Agents/chemistry , Antifungal Agents/pharmacokinetics , Antifungal Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , COVID-19/drug therapy , Cell Line, Tumor , Coronavirus 3C Proteases/chemistry , Galactose/chemistry , Galactose/pharmacokinetics , Galactose/pharmacology , Gram-Positive Bacteria/drug effects , Mice , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2/enzymology , Static Electricity , Thermodynamics
4.
Sci Rep ; 11(1): 15431, 2021 07 29.
Article in English | MEDLINE | ID: covidwho-1332853

ABSTRACT

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.


Subject(s)
Epitopes/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , Vaccines/immunology , Computational Biology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Epitopes, B-Lymphocyte/genetics , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , Humans , Immunogenicity, Vaccine/immunology , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Models, Molecular , Molecular Docking Simulation , Phylogeny , Protein Binding , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Helper-Inducer/immunology , Vaccines/pharmacology , Vaccines, DNA , Vaccines, Subunit/immunology , Viral Vaccines/immunology
5.
Brief Bioinform ; 22(2): 1402-1414, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343661

ABSTRACT

The new coronavirus (SARS-CoV-2) halts the world economy and caused unbearable medical emergency due to high transmission rate and also no effective vaccine and drugs has been developed which brought the world pandemic situations. The main protease (Mpro) of SARS-CoV-2 may act as an effective target for drug development due to the conservation level. Herein, we have employed a rigorous literature review pipeline to enlist 3063 compounds from more than 200 plants from the Asian region. Therefore, the virtual screening procedure helps us to shortlist the total compounds into 19 based on their better binding energy. Moreover, the Prime MM-GBSA procedure screened the compound dataset further where curcumin, gartanin and robinetin had a score of (-59.439, -52.421 and - 47.544) kcal/mol, respectively. The top three ligands based on binding energy and MM-GBSA scores have most of the binding in the catalytic groove Cys145, His41, Met165, required for the target protein inhibition. The molecular dynamics simulation study confirms the docked complex rigidity and stability by exploring root mean square deviations, root mean square fluctuations, solvent accessible surface area, radius of gyration and hydrogen bond analysis from simulation trajectories. The post-molecular dynamics analysis also confirms the interactions of the curcumin, gartanin and robinetin in the similar binding pockets. Our computational drug designing approach may contribute to the development of drugs against SARS-CoV-2.


Subject(s)
COVID-19/virology , Plants/chemistry , Protease Inhibitors/metabolism , SARS-CoV-2/enzymology , Humans , Molecular Dynamics Simulation
6.
Biology (Basel) ; 10(7)2021 Jun 26.
Article in English | MEDLINE | ID: covidwho-1288800

ABSTRACT

Currently, a worldwide pandemic has been declared in response to the spread of coronavirus disease 2019 (COVID-19), a fatal and fast-spreading viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The low availability of efficient vaccines and treatment options has resulted in a high mortality rate, bringing the world economy to its knees. Thus, mechanistic investigations of drugs capable of counteracting this disease are in high demand. The main protease (Mpro) expressed by SARS-CoV-2 has been targeted for the development of potential drug candidates due to the crucial role played by Mpro in viral replication and transcription. We generated a phytochemical library containing 1672 phytochemicals derived from 56 plants, which have been reported as having antiviral, antibacterial, and antifungal activity. A molecular docking program was used to screen the top three candidate compounds: epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate, which had respective binding affinities of -8.4, -8.5, and -8.8 kcal/mol. Several active sites in the targeted protein, including Cys145, His41, Met49, Glu66, and Met165, were found to interact with the top three candidate compounds. The multiple simulation profile, root-mean-square deviation, root-mean-square fluctuation, radius of gyration, and solvent-accessible surface area values supported the inflexible nature of the docked protein-compound complexes. The toxicity and carcinogenicity profiles were assessed, which showed that epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate had favorable pharmacological properties with no adverse effects. These findings suggest that these compounds could be developed as part of an effective drug development pathway to treat COVID-19.

7.
Front Mol Biosci ; 8: 628585, 2021.
Article in English | MEDLINE | ID: covidwho-1247880

ABSTRACT

The recently emerged coronavirus (SARS-CoV-2) has created a crisis in world health, and economic sectors as an effective treatment or vaccine candidates are still developing. Besides, negative results in clinical trials and effective cheap solution against this deadly virus have brought new challenges. The viral protein, the main protease from SARS-CoV-2, can be effectively targeted due to its viral replication and pathogenesis role. In this study, we have enlisted 88 peptides from the AVPdb database. The peptide molecules were modeled to carry out the docking interactions. The four peptides molecules, P14, P39, P41, and P74, had more binding energy than the rest of the peptides in multiple docking programs. Interestingly, the active points of the main protease from SARS-CoV-2, Cys145, Leu141, Ser139, Phe140, Leu167, and Gln189, showed nonbonded interaction with the peptide molecules. The molecular dynamics simulation study was carried out for 200 ns to find out the docked complex's stability where their stability index was proved to be positive compared to the apo and control complex. Our computational works based on peptide molecules may aid the future development of therapeutic options against SARS-CoV-2.

8.
Molecules ; 26(8)2021 Apr 12.
Article in English | MEDLINE | ID: covidwho-1178366

ABSTRACT

The recent coronavirus disease 2019 (COVID-19) pandemic is a global threat for healthcare management and the economic system, and effective treatments against the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for this disease have not yet progressed beyond the developmental phases. As drug refinement and vaccine progression require enormously broad investments of time, alternative strategies are urgently needed. In this study, we examined phytochemicals extracted from Avicennia officinalis and evaluated their potential effects against the main protease of SARS-CoV-2. The antioxidant activities of A. officinalis leaf and fruit extracts at 150 µg/mL were 95.97% and 92.48%, respectively. Furthermore, both extracts displayed low cytotoxicity levels against Artemia salina. The gas chromatography-mass spectroscopy analysis confirmed the identifies of 75 phytochemicals from both extracts, and four potent compounds, triacontane, hexacosane, methyl linoleate, and methyl palminoleate, had binding free energy values of -6.75, -6.7, -6.3, and -6.3 Kcal/mol, respectively, in complexes with the SARS-CoV-2 main protease. The active residues Cys145, Met165, Glu166, Gln189, and Arg188 in the main protease formed non-bonded interactions with the screened compounds. The root-mean-square difference (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond data from a molecular dynamics simulation study confirmed the docked complexes' binding rigidity in the atomistic simulated environment. However, this study's findings require in vitro and in vivo validation to ensure the possible inhibitory effects and pharmacological efficacy of the identified compounds.


Subject(s)
Avicennia/chemistry , COVID-19/drug therapy , Phytochemicals/therapeutic use , SARS-CoV-2/metabolism , Antioxidants/chemistry , Antioxidants/metabolism , Antioxidants/therapeutic use , Avicennia/metabolism , Binding Sites , COVID-19/pathology , COVID-19/virology , Fruit/chemistry , Fruit/metabolism , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Phenylethyl Alcohol/chemistry , Phenylethyl Alcohol/metabolism , Phenylethyl Alcohol/therapeutic use , Phenylpropionates/chemistry , Phenylpropionates/metabolism , Phenylpropionates/therapeutic use , Phytochemicals/chemistry , Phytochemicals/metabolism , Plant Leaves/chemistry , Plant Leaves/metabolism , SARS-CoV-2/isolation & purification , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/metabolism
9.
J Biomol Struct Dyn ; 40(5): 2067-2081, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-885576

ABSTRACT

COVID-19 and its causative organism SARS-CoV2 that emerged from Wuhan city, China have paralyzed the world. With no clinically approved drugs, the global health system is struggling to find an effective treatment measure. At this crucial juncture, screening of plant-derived compounds may be an effective strategy to combat COVID-19. The present study investigated the binding affinity of phytocompounds with 3-Chymotrypsin-like (3CLpro) and Papain-like proteases (PLpro) of SARS-CoV2 using in-silico techniques. A total of 32 anti-protease phytocompounds were investigated for the binding affinity to the proteins. Docking was performed in Autodock Vina. Pharmacophore descriptors of best ligands were studied using LigandScout. Molecular dynamics (MD) simulation of apo-protein and ligand-bound complexes was carried out in YASARA software. The druglikeness properties of phytocompounds were studied using ADMETlab. Out of 32 phytochemicals, amentoflavone and gallocatechin gallate showed the best binding affinity to 3CLpro (-9.4 kcal/mol) and PLpro (-8.8 kcal/mol). Phytochemicals such as savinin, theaflavin-3,3-digallate, and kazinol-A also showed strong affinity. MD simulation revealed ligand-induced conformational changes in the protein with decreased surface area and higher stability. The RMSD/F of proteins and ligands showed stability of the protein suggesting the effective binding of the ligand in both the proteins. Both amentoflavone and gallocatechin gallate possess promising druglikeness property. The present study thus suggests that Amentoflavone and Gallocatechin gallate may be potential inhibitors of 3CLpro and PLpro proteins and effective drug candidates for SARS-CoV2. However, the findings of in silico study need to be supported by in vivo studies to establish the exact mode of action.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , Chymotrypsin , Humans , Molecular Docking Simulation , Papain , Peptide Hydrolases , Phytochemicals/pharmacology , RNA, Viral , SARS-CoV-2
10.
J Biomol Struct Dyn ; 39(16): 6281-6289, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-670995

ABSTRACT

Newly emerged SARS-CoV-2 made recent pandemic situations across the globe is accountable for countless unwanted death and insufferable panic associated with co-morbidities among mass people. The scarcity of appropriate medical treatment and no effective vaccine or medicine against SARS-CoV-2 has turned the situation worst. Therefore, in this study, we made a deep literature review to enlist plant-derived natural compounds and considered their binding mechanism with the main protease of SARS-CoV-2 through combinatorial bioinformatics approaches. Among all, a total of 14 compounds were filtered where Carinol, Albanin, Myricetin were had better binding profile than the rest of the compounds with having binding energy of -8.476, -8.036, -8.439 kcal/mol, respectively. Furthermore, MM-GBSA calculations were also considered in this selection process to support docking studies. Besides, 100 ns molecular dynamics simulation endorsed the rigid nature, less conformational variation and binding stiffness. As this study, represents a perfect model for SARS-CoV-2 main protease inhibition through bioinformatics study, these potential drug candidates may assist the researchers to find a superior and effective solution against COVID-19 after future experiments.Communicated by Ramaswamy Sarma.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Hydrolases , Protease Inhibitors
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