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1.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 39(5): 1005-1014, 2022 Oct 25.
Article in Chinese | MEDLINE | ID: covidwho-2100336

ABSTRACT

We aim to screen out the active components that may have therapeutic effect on coronavirus disease 2019 (COVID-19) from the severe and critical cases' prescriptions in the "Coronavirus Disease 2019 Diagnosis and Treatment Plan (Trial Ninth Edition)" issued by the National Health Commission of the People's Republic of China and explain its mechanism through the interactions with proteins. The ETCM database and SwissADME database were used to screen the active components contained in 25 traditional Chinese medicines in 3 prescriptions, and the PDB database was used to obtain the crystal structures of 4 proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molecular docking was performed using Autodock Vina and molecular dynamics simulations were performed using GROMACS. Binding energy results showed that 44 active ingredients including xambioona, gancaonin L, cynaroside, and baicalin showed good binding affinity with multiple targets of SARS-CoV-2, while molecular dynamics simulations analysis showed that xambioona bound more tightly to the nucleocapsid protein of SARS-CoV-2 and exerted a potent inhibitory effect. Modern technical methods are used to study the active components of traditional Chinese medicine and show that xambioona is an effective inhibitor of SARS-CoV-2 nucleocapsid protein, which provides a theoretical basis for the development of new anti-SARS-CoV-2 drugs and their treatment methods.


Subject(s)
COVID-19 , Humans , COVID-19/drug therapy , SARS-CoV-2 , Molecular Docking Simulation , Medicine, Chinese Traditional , Molecular Dynamics Simulation , Nucleocapsid Proteins , Antiviral Agents/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/pharmacology
2.
Molecules ; 27(21)2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2099670

ABSTRACT

Since there is an urgent need for novel treatments to combat the current coronavirus disease 2019 (COVID-19) pandemic, in silico molecular docking studies were implemented as an attempt to explore the ability of selected bioactive constituents of extra virgin olive oil (EVOO) to act as potent SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antiviral compounds, aiming to explore their ability to interact with SARS-CoV-2 Spike key therapeutic target protein. Our results suggest that EVOO constituents display substantial capacity for binding and interfering with Spike (S) protein, both wild-type and mutant, via the receptor-binding domain (RBD) of Spike, or other binding targets such as angiotensin-converting enzyme 2 (ACE2) or the RBD-ACE2 protein complex, inhibiting the interaction of the virus with host cells. This in silico study provides useful insights for the understanding of the mechanism of action of the studied compounds at a molecular level. From the present study, it could be suggested that the studied active phytochemicals could potentially inhibit the Spike protein, contributing thus to the understanding of the role that they can play in future drug designing and the development of anti-COVID-19 therapeutics.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Olive Oil , Molecular Docking Simulation , COVID-19/drug therapy , Peptidyl-Dipeptidase A/metabolism , Binding Sites , Protein Binding
3.
Molecules ; 27(21)2022 Oct 31.
Article in English | MEDLINE | ID: covidwho-2099665

ABSTRACT

Synthesis of sulfonamide through an indirect method that avoids contamination of the product with no need for purification has been carried out using the indirect process. Here, we report the synthesis of a novel sulfonamide compound, ({4-nitrophenyl}sulfonyl)tryptophan (DNSPA) from 4-nitrobenzenesulphonylchloride and L-tryptophan precursors. The slow evaporation method was used to form single crystals of the named compound from methanolic solution. The compound was characterized by X-ray crystallographic analysis and spectroscopic methods (NMR, IR, mass spectrometry, and UV-vis). The sulfonamide N-H NMR signal at 8.07-8.09 ppm and S-N stretching vibration at 931 cm-1 indicate the formation of the target compound. The compound crystallized in the monoclinic crystal system and P21 space group with four molecules of the compound in the asymmetric unit. Molecular aggregation in the crystal structure revealed a 12-molecule aggregate synthon sustained by O-H⋯O hydrogen bonds and stabilised by N-H⋯O intermolecular contacts. Experimental studies were complemented by DFT calculations at the B3LYP/6-311++G(d,p) level of theory. The computed structural and spectroscopic data are in good agreement with those obtained experimentally. The energies of interactions between the units making up the molecule were calculated. Molecular docking studies showed that DNSPA has a binding energy of -6.37 kcal/mol for E. coli DNA gyrase (5MMN) and -6.35 kcal/mol for COVID-19 main protease (6LU7).


Subject(s)
COVID-19 , Tryptophan , Humans , Quantum Theory , Models, Molecular , Molecular Docking Simulation , Escherichia coli , Spectroscopy, Fourier Transform Infrared , Sulfonamides
4.
SAR QSAR Environ Res ; 33(10): 753-778, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2096975

ABSTRACT

Since interleukin-8 (IL-8/CXCL8) and its receptor, CXCR1 and CXCR2, were known in the early 1990s, biological pathways related to these proteins were proven to have high clinical value in cancer and inflammatory/autoimmune conditions treatment. Recently, IL-8 has been identified as biomarker for severe COVID-19 patients and COVID-19 prognosis. Boyles et al. (mAbs 12 (2020), pp. 1831880) have published a high-resolution X-ray crystal structure of the LY3041658 Fab in a complex human CXCL8. They described the ability to bind to IL-8 and the blocking of IL-8/its receptors interaction by the LY3041658 monoclonal antibody. Therefore, the study has been designed to identify potential small molecules inhibiting interleukin-8 by targeting LY3041658/IL-8 complex structure using an in silico approach. A structure­based pharmacophore and molecular docking models of the protein active site cavity were generated to identify possible candidates, followed by virtual screening with the ZINC database. ADME analysis of hit compounds was also conducted. Molecular dynamics simulations were then performed to survey the behaviour and stability of the ligand-protein complexes. Furthermore, the MM/PBSA technique has been utilized to evaluate the free binding energy. The final data confirmed that one newly obtained compound, ZINC21882765, may serve as the best potential inhibitor for IL-8.


Subject(s)
COVID-19 , Interleukin-8 , Humans , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , COVID-19/drug therapy , Molecular Dynamics Simulation , Ligands
5.
Molecules ; 27(21)2022 Oct 29.
Article in English | MEDLINE | ID: covidwho-2090288

ABSTRACT

Chemical investigation of the total extract of the Egyptian soft coral Heteroxenia fuscescens, led to the isolation of eight compounds, including two new metabolites, sesquiterpene fusceterpene A (1) and a sterol fuscesterol A (4), along with six known compounds. The structures of 1-8 were elucidated via intensive studies of their 1D, 2D-NMR, and HR-MS analyses, as well as a comparison of their spectral data with those mentioned in the literature. Subsequent comprehensive in-silico-based investigations against almost all viral proteins, including those of the new variants, e.g., Omicron, revealed the most probable target for these isolated compounds, which was found to be Mpro. Additionally, the dynamic modes of interaction of the putatively active compounds were highlighted, depending on 50-ns-long MDS. In conclusion, the structural information provided in the current investigation highlights the antiviral potential of H. fuscescens metabolites with 3ß,5α,6ß-trihydroxy steroids with different nuclei against SARS-CoV-2, including newly widespread variants.


Subject(s)
Anthozoa , COVID-19 , Animals , SARS-CoV-2 , COVID-19/drug therapy , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Anthozoa/chemistry , Sterols , Molecular Docking Simulation , Molecular Dynamics Simulation
6.
Molecules ; 27(21)2022 Oct 28.
Article in English | MEDLINE | ID: covidwho-2090287

ABSTRACT

The rapid spread of SARS-CoV-2 required immediate actions to control the transmission of the virus and minimize its impact on humanity. An extensive mutation rate of this viral genome contributes to the virus' ability to quickly adapt to environmental changes, impacts transmissibility and antigenicity, and may facilitate immune escape. Therefore, it is of great interest for researchers working in vaccine development and drug design to consider the impact of mutations on virus-drug interactions. Here, we propose a multitarget drug discovery pipeline for identifying potential drug candidates which can efficiently inhibit the Receptor Binding Domain (RBD) of spike glycoproteins from different variants of SARS-CoV-2. Eight homology models of RBDs for selected variants were created and validated using reference crystal structures. We then investigated interactions between host receptor ACE2 and RBDs from nine variants of SARS-CoV-2. It led us to conclude that efficient multi-variant targeting drugs should be capable of blocking residues Q(R)493 and N487 in RBDs. Using methods of molecular docking, molecular mechanics, and molecular dynamics, we identified three lead compounds (hesperidin, narirutin, and neohesperidin) suitable for multitarget SARS-CoV-2 inhibition. These compounds are flavanone glycosides found in citrus fruits - an active ingredient of Traditional Chinese Medicines. The developed pipeline can be further used to (1) model mutants for which crystal structures are not yet available and (2) scan a more extensive library of compounds against other mutated viral proteins.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/genetics , Molecular Dynamics Simulation , Molecular Docking Simulation , Receptors, Virus/metabolism , COVID-19/drug therapy , Protein Binding , Glycoproteins/metabolism , Mutation
7.
Molecules ; 27(21)2022 Oct 28.
Article in English | MEDLINE | ID: covidwho-2090285

ABSTRACT

The emergence of immune-evading variants of SARS-CoV-2 further aggravated the ongoing pandemic. Despite the deployments of various vaccines, the acquired mutations are capable of escaping both natural and vaccine-induced immune responses. Therefore, further investigation is needed to design a decisive pharmacological treatment that could efficiently block the entry of this virus into cells. Hence, the current study used structure-based methods to target the RBD of the recombinant variant (Deltacron) of SARS-CoV-2, which was used as a model variant. From the virtual drug screenings of various databases, a total of four hits were identified as potential lead molecules. Key residues were blocked by these molecules with favorable structural dynamic features. The binding free energies further validated the potentials of these molecules. The TBE for MNP was calculated to be -32.86 ± 0.10 kcal/mol, for SANC00222 the TBE was -23.41 ± 0.15 kcal/mol, for Liriodenine the TBE was -34.29 ± 0.07 kcal/mol, while for Carviolin the TBE was calculated to be -27.67 ± 0.12 kcal/mol. Moreover, each complex demonstrated distinct internal motion and a free energy profile, indicating a different strategy for the interaction with and inhibition of the RBD. In conclusion, the current study demands further in vivo and in vitro validation for the possible usage of these compounds as potential drugs against SARS-CoV-2 and its variants.


Subject(s)
COVID-19 , Viral Vaccines , Humans , SARS-CoV-2 , COVID-19/drug therapy , Pandemics , Protein Binding , Molecular Docking Simulation
8.
Int J Mol Sci ; 23(20)2022 Oct 19.
Article in English | MEDLINE | ID: covidwho-2082081

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2), a functional receptor for SARS-CoV, now appears likely to mediate 2019-nCoV entry into human cells. However, inhibitors such as PAP-1 and bergamottin have been discovered; both of them can preferentially bind to ACE2, prevent RBD Spike S protein from binding to ACE2, and reduce the binding sites for RBD Spike S protein. In addition, we investigated the binding energy of PAP-1 and bergamottin with ACE2 through molecular docking with bio-layer interferometry (BLI) and found relatively high binding affinity (KD = 48.5 nM, 53.1 nM) between the PAP-1 and bergamottin groups. In addition, the nanomolar fraction had no effect on growth of the AT-II cell, but 150 µM PAP-1 and 75 µM bergamottin inhibited the proliferation of AT-II cells in vitro by 75% and 68%, respectively. Meanwhile, they significantly reduced ACE2 mRNA and proteins by 67%, 58% and 55%, 41%, respectively. These results indicate that psoralen compounds PAP-1 and bergamottin binding to ACE2 protein could be further developed in the fight against COVID-19 infection during the current pandemic. However, attention should be paid to the damage to human alveolar type II epithelial cells.


Subject(s)
COVID-19 , Furocoumarins , Humans , Angiotensin-Converting Enzyme 2 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Molecular Docking Simulation , COVID-19/drug therapy , Peptidyl-Dipeptidase A/metabolism , Furocoumarins/pharmacology , RNA, Messenger/metabolism , Protein Binding
9.
Molecules ; 27(20)2022 Oct 18.
Article in English | MEDLINE | ID: covidwho-2081847

ABSTRACT

Griseofulvin is an antifungal polyketide metabolite produced mainly by ascomycetes. Since it was commercially introduced in 1959, griseofulvin has been used in treating dermatophyte infections. This fungistatic has gained increasing interest for multifunctional applications in the last decades due to its potential to disrupt mitosis and cell division in human cancer cells and arrest hepatitis C virus replication. In addition to these inhibitory effects, we and others found griseofulvin may enhance ACE2 function, contribute to vascular vasodilation, and improve capillary blood flow. Furthermore, molecular docking analysis revealed that griseofulvin and its derivatives have good binding potential with SARS-CoV-2 main protease, RNA-dependent RNA polymerase (RdRp), and spike protein receptor-binding domain (RBD), suggesting its inhibitory effects on SARS-CoV-2 entry and viral replication. These findings imply the repurposing potentials of the FDA-approved drug griseofulvin in designing and developing novel therapeutic interventions. In this review, we have summarized the available information from its discovery to recent progress in this growing field. Additionally, explored is the possible mechanism leading to rare hepatitis induced by griseofulvin. We found that griseofulvin and its metabolites, including 6-desmethylgriseofulvin (6-DMG) and 4- desmethylgriseofulvin (4-DMG), have favorable interactions with cytokeratin intermediate filament proteins (K8 and K18), ranging from -3.34 to -5.61 kcal mol-1. Therefore, they could be responsible for liver injury and Mallory body (MB) formation in hepatocytes of human, mouse, and rat treated with griseofulvin. Moreover, the stronger binding of griseofulvin to K18 in rodents than in human may explain the observed difference in the severity of hepatitis between rodents and human.


Subject(s)
COVID-19 , Polyketides , Mice , Humans , Rats , Animals , Griseofulvin/pharmacology , Antifungal Agents/pharmacology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Molecular Docking Simulation , Spike Glycoprotein, Coronavirus , Keratins/metabolism , RNA-Dependent RNA Polymerase
10.
Molecules ; 27(20)2022 Oct 17.
Article in English | MEDLINE | ID: covidwho-2071653

ABSTRACT

The tracing of an alternative drug, Phytochemicals is a promising approach to the viral threats that have emerged over the past two years. Across the world, herbal medicine is a better solution against anti-viral diseases during pandemic periods. Goniothalamus wightii is an herbal plant, which has diverse bioactive compounds with anticancer, antioxidant, and anti-viral properties. The aim of the study was to isolate the compound by chromatography studies and functionalization by FT-IR, LC-MS, and NMR (C-NMR, H-NMR). As a result, the current work focuses on whether (S)-Goniathalamin and its analogue could act as natural anti-viral molecules for multiple target proteins viz., MPro, RdRp, and SPro, which are required for SARS-CoV-2 infection. Overall, 954 compounds were examined and the molecular-docking studies were performed on the maestro platform of Schrodinger software. Molecular-dynamics simulation studies were performed on two complex major compounds to confirm their affinity across 150 simulations. This research suggests that plant-based drugs have high levels of antiviral properties against coronavirus. However, more research is needed to verify its antiviral properties.


Subject(s)
COVID-19 , Goniothalamus , Humans , SARS-CoV-2 , COVID-19/drug therapy , Coronavirus 3C Proteases , Antioxidants , Spectroscopy, Fourier Transform Infrared , Cysteine Endopeptidases/chemistry , Antiviral Agents/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , RNA-Dependent RNA Polymerase
11.
Molecules ; 27(20)2022 Oct 12.
Article in English | MEDLINE | ID: covidwho-2071650

ABSTRACT

COVID-19 can cause different neurological symptoms in some people, including smell, inability to taste, dizziness, confusion, delirium, seizures, stroke, etc. Owing to the issue of vaccine effectiveness, update and coverage, we still need one or more diversified strategies as the backstop to manage illness. Characterizing the structural basis of ligand recognition in the main protease (Mpro) of SARS-CoV-2 will facilitate its rational design and development of potential drug candidates with high affinity and selectivity against COVID-19. Up to date, covalent-, non-covalent inhibitors and allosteric modulators have been reported to bind to different active sites of Mpro. In the present work, we applied the molecular dynamics (MD) simulations to systematically characterize the potential binding features of catalytic active site and allosteric binding sites in Mpro using a dataset of 163 3D structures of Mpro-inhibitor complexes, in which our results are consistent with the current studies. In addition, umbrella sampling (US) simulations were used to explore the dissociation processes of substrate pathway and allosteric pathway. All the information provided new insights into the protein features of Mpro and will facilitate its rational drug design for COVID-19.


Subject(s)
COVID-19 , Molecular Dynamics Simulation , Humans , SARS-CoV-2 , COVID-19/drug therapy , Ligands , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/metabolism , Coronavirus 3C Proteases , Molecular Docking Simulation , Antiviral Agents/pharmacology , Antiviral Agents/chemistry
12.
Int J Mol Sci ; 23(20)2022 Oct 13.
Article in English | MEDLINE | ID: covidwho-2071505

ABSTRACT

In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated the highest binding affinities towards SARS-CoV-2 Mpro. A molecular dynamics study at 200 ns was also carried out for the most promising anticoagulants to provide insights into the dynamic and thermodynamic properties of promising compounds. Moreover, a quantum mechanical study was also conducted which helped us to attest to some of the molecular docking and dynamics findings. A biological evaluation (in vitro) of the most promising compounds was also performed by carrying out the MTT cytotoxicity assay and the crystal violet assay in order to assess inhibitory concentration 50 (IC50). It is worth noting that ticagrelor displayed the highest intrinsic potential for the inhibition of SARS-CoV-2 with an IC50 value of 5.60 µM and a safety index of 25.33. In addition, fondaparinux sodium and dabigatran showed promising inhibitory activities with IC50 values of 8.60 and 9.40 µM, respectively, and demonstrated safety indexes of 17.60 and 15.10, respectively. Moreover, the inhibitory potential of the SARS-CoV-2 Mpro enzyme was investigated by utilizing the SARS-CoV-2 Mpro assay and using tipranavir as a reference standard. Interestingly, promising SARS-CoV-2 Mpro inhibitory potential was attained for fondaparinux sodium with an IC50 value of 2.36 µM, surpassing the reference tipranavir (IC50 = 7.38 µM) by more than three-fold. Furthermore, highly eligible SARS-CoV-2 Mpro inhibitory potential was attained for dabigatran with an IC50 value of 10.59 µM. Finally, an SAR was discussed, counting on the findings of both in vitro and in silico approaches.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/drug therapy , Molecular Docking Simulation , Coronavirus 3C Proteases , Molecular Dynamics Simulation , Fondaparinux , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Dabigatran , Ticagrelor , Eptifibatide , Gentian Violet , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/metabolism , Heparin/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/chemistry
13.
Int J Mol Sci ; 23(18)2022 Sep 19.
Article in English | MEDLINE | ID: covidwho-2071502

ABSTRACT

The chymotrypsin-like cysteine protease (3CLpro, also known as main protease-Mpro) and papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been used as the main targets for screening potential synthetic inhibitors for posterior in vitro evaluation of the most promising compounds. In this sense, the present work reports for the first time the evaluation of the interaction between Mpro/PLpro with a series of 17 porphyrin analogues-corrole (C1), meso-aryl-corrole (C2), and 15 fluorinated-meso-aryl-corrole derivatives (C3-C17) via molecular docking calculations. The impact of fluorine atoms on meso-aryl-corrole structure was also evaluated in terms of binding affinity and physical-chemical properties by two-dimensional quantitative structure-activity relationship (2D-QSAR). The presence of phenyl moieties increased the binding capacity of corrole for both proteases and depending on the position of fluorine atoms might impact positively or negatively the binding capacity. For Mpro the para-fluorine atoms might decrease drastically the binding capacity, while for PLpro there was a certain increase in the binding affinity of fluorinated-corroles with the increase of fluorine atoms into meso-aryl-corrole structure mainly from tri-fluorinated insertions. The 2D-QSAR models indicated two separated regions of higher and lower affinity for Mpro:C1-C17 based on dual electronic parameters (σI and σR), as well as one model was obtained with a correlation between the docking score value of Mpro:C2-C17 and the corresponding 13C nuclear magnetic resonance (NMR) chemical shifts of the sp2 carbon atoms (δC-1 and δC-2) of C2-C17. Overall, the fluorinated-meso-aryl-corrole derivatives showed favorable in silico parameters as potential synthetic compounds for future in vitro assays on the inhibition of SARS-CoV-2 replication.


Subject(s)
COVID-19 , Porphyrins , Antiviral Agents/pharmacology , COVID-19/drug therapy , Carbon , Chymotrypsin , Coronavirus 3C Proteases , Fluorine , Humans , Molecular Docking Simulation , Papain , Peptide Hydrolases , Porphyrins/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Quantitative Structure-Activity Relationship , SARS-CoV-2
14.
Biosensors (Basel) ; 12(10)2022 Oct 17.
Article in English | MEDLINE | ID: covidwho-2071230

ABSTRACT

In March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic, and the spike protein has been reported to be an important drug target for anti-COVID-19 treatment. As such, in this study, we successfully developed a novel electrochemical receptor biosensor by immobilizing the SARS-CoV-2 spike protein and using AuNPs-HRP as an electrochemical signal amplification system. Moreover, the time-current method was used to quantify seven antiviral drug compounds, such as arbidol and chloroquine diphosphate. The results show that the spike protein and the drugs are linearly correlated within a certain concentration range and that the detection sensitivity of the sensor is extremely high. In the low concentration range of linear response, the kinetics of receptor-ligand interactions are similar to that of an enzymatic reaction. Among the investigated drug molecules, bromhexine exhibits the smallest Ka value, and thus, is most sensitively detected by the sensor. Hydroxychloroquine exhibits the largest Ka value. Molecular docking simulations of the spike protein with six small-molecule drugs show that residues of this protein, such as Asp, Trp, Asn, and Gln, form hydrogen bonds with the -OH or -NH2 groups on the branched chains of small-molecule drugs. The electrochemical receptor biosensor can directly quantify the interaction between the spike protein and drugs such as abidor and hydroxychloroquine and perform kinetic studies with a limit of detection 3.3 × 10-20 mol/L, which provides a new research method and idea for receptor-ligand interactions and pharmacodynamic evaluation.


Subject(s)
Bromhexine , COVID-19 , Metal Nanoparticles , Humans , Spike Glycoprotein, Coronavirus/chemistry , Hydroxychloroquine/pharmacology , SARS-CoV-2 , Molecular Docking Simulation , Kinetics , Ligands , Gold , Antiviral Agents/pharmacology
15.
Front Immunol ; 13: 918476, 2022.
Article in English | MEDLINE | ID: covidwho-2071085

ABSTRACT

Background: Deep venous thrombosis (DVT) highly occurs in patients with severe COVID-19 and probably accounted for their high mortality. DVT formation is a time-dependent inflammatory process in which NETosis plays an important role. However, whether ginsenoside Rg5 from species of Panax genus could alleviate DVT and its underlying mechanism has not been elucidated. Methods: The interaction between Rg5 and P2RY12 was studied by molecular docking, molecular dynamics, surface plasmon resonance (SPR), and molecular biology assays. The preventive effect of Rg5 on DVT was evaluated in inferior vena cava stasis-induced mice, and immunocytochemistry, Western blot, and calcium flux assay were performed in neutrophils from bone marrow to explore the mechanism of Rg5 in NETosis via P2RY12. Results: Rg5 allosterically interacted with P2RY12, formed stable complex, and antagonized its activity via residue E188 and R265. Rg5 ameliorated the formation of thrombus in DVT mice; accompanied by decreased release of Interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α in plasma; and suppressed neutrophil infiltration and neutrophil extracellular trap (NET) release. In lipopolysaccharide- and platelet-activating factor-induced neutrophils, Rg5 reduced inflammatory responses via inhibiting the activation of ERK/NF-κB signaling pathway while decreasing cellular Ca2+ concentration, thus reducing the activity and expression of peptidyl arginine deiminase 4 to prevent NETosis. The inhibitory effect on neutrophil activity was dependent on P2RY12. Conclusions: Rg5 could attenuate experimental DVT by counteracting NETosis and inflammatory response in neutrophils via P2RY12, which may pave the road for its clinical application in the prevention of DVT-related disorders.


Subject(s)
COVID-19 , Venous Thrombosis , Animals , Ginsenosides , Mice , Molecular Docking Simulation , Neutrophils
16.
Cell Mol Biol (Noisy-le-grand) ; 68(6): 31-35, 2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-2067350

ABSTRACT

It has been seen that, during COVID-19 outbreak lung cancer (LC) patients are noted as a high-risk population which make a more challenging to treatment of the LC patients. The active form of caspase-8 is involved in lung carcinogenesis in both humans and mice. In this study, the virtual screening was performed among 200 compounds retrieved from several resources for the searching of potent lead against Caspase 8 (Casp8). Cryptophycin 52 was found to have a strong inhibiting efficacy based on the free energy of binding with the active site of Casp8. The lowest binding energy was found to be -8.05 kcal/mole and was further analyzed for molecular dynamic simulation. Casp8 enzyme was determined to interact with cryptophycin 52 through twelve amino acid residues, specifically ARG260, SER316, GLY318, ASP319, THR337, VAL354, PHE355, PHE356, ILE357, GLN358, ALA359 and CYS360 along with six hydrogen bond particular, ILE357:N-UNK1: O7, UNK1: O14-PHE355:O, UNK1: C25-PHE355:O, UNK1: C35-THR337:O, UNK1: H65-HE355:O and UNK1: C25-PHE356. In addition, MD simulations for 50ns were performed for optimization, flexibility estimation and assessment of Casp8-cryptophycin 52 complex stability. This complex was seen as reasonably stable according to the RMSD, RMSF, and radius of gyration graph. Results obtained indicate cryptophycin 52 may be a lead compound with significant anti-cancer ability against Casp8. Further experimental work, however, is expected to support the compound's anti-cancer viewpoint.


Subject(s)
COVID-19 , Lung Neoplasms , Amino Acids , Animals , COVID-19/drug therapy , Caspase 8 , Depsipeptides , Disease Outbreaks , Humans , Lactams , Lactones , Lung Neoplasms/drug therapy , Mice , Molecular Docking Simulation , Molecular Dynamics Simulation
17.
Viruses ; 14(10)2022 09 29.
Article in English | MEDLINE | ID: covidwho-2066548

ABSTRACT

In order to test the antiviral activity, a series of usnic acid derivatives were synthesized, including new, previously undescribed compounds. The activity of the derivatives against three strains of SARS-CoV-2 virus was studied. To understand the mechanism of antiviral action, the inhibitory activity of the main protease of SARS-CoV-2 virus was studied using the developed model as well as the antiviral activity against the pseudoviral system with glycoprotein S of SARS-CoV-2 virus on its surface. It was shown that usnic acid exhibits activity against three strains of SARS-CoV-2 virus: Wuhan, Delta, and Omicron. Compounds 10 and 13 also showed high activity against the three strains. The performed biological studies and molecular modeling allowed us to assume that the derivatives of usnic acid bind in the N-terminal domain of the surface glycoprotein S at the binding site of the hemoglobin decay metabolite.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Protease Inhibitors/pharmacology , Molecular Docking Simulation , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Peptide Hydrolases , Membrane Glycoproteins
18.
Molecules ; 27(19)2022 Oct 09.
Article in English | MEDLINE | ID: covidwho-2066287

ABSTRACT

The main protease enzyme (Mpro) of SARS-CoV-2 is one of the most promising targets for COVID-19 treatment. Accordingly, in this work, a structure-based virtual screening of 3.8 million ligand libraries was carried out. After rigorous filtering, docking, and post screening assessments, 78 compounds were selected for biological evaluation, 3 of which showed promising inhibition of the Mpro enzyme. The obtained hits (CB03, GR04, and GR20) had reasonable potencies with Ki values in the medium to high micromolar range. Interestingly, while our most potent hit, GR20, was suggested to act via a reversible covalent mechanism, GR04 was confirmed as a noncompetitive inhibitor that seems to be one of a kind when compared to the other allosteric inhibitors discovered so far. Moreover, all three compounds have small sizes (~300 Da) with interesting fittings in their relevant binding sites, and they possess lead-like characteristics that can introduce them as very attractive candidates for the future development of COVID-19 treatments.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Catalytic Domain , Coronavirus 3C Proteases , Humans , Ligands , Molecular Docking Simulation , Protease Inhibitors/chemistry
19.
Molecules ; 27(19)2022 Oct 01.
Article in English | MEDLINE | ID: covidwho-2066282

ABSTRACT

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has stressed the global health system to a significant level, which has not only resulted in high morbidity and mortality but also poses a threat for future pandemics. This situation warrants efforts to develop novel therapeutics to manage SARS-CoV-2 in specific and other emerging viruses in general. This study focuses on SARS-CoV2 RNA-dependent RNA polymerase (RdRp) mutations collected from Saudi Arabia and their impact on protein structure and function. The Saudi SARS-CoV-2 RdRp sequences were compared with the reference Wuhan, China RdRp using a variety of computational and biophysics-based approaches. The results revealed that three mutations-A97V, P323I and Y606C-may affect protein stability, and hence the relationship of protein structure to function. The apo wild RdRp is more dynamically stable with compact secondary structure elements compared to the mutants. Further, the wild type showed stable conformational dynamics and interaction network to remdesivir. The net binding energy of wild-type RdRp with remdesivir is -50.76 kcal/mol, which is more stable than the mutants. The findings of the current study might deliver useful information regarding therapeutic development against the mutant RdRp, which may further furnish our understanding of SARS-CoV-2 biology.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/genetics , Humans , Molecular Docking Simulation , Mutation , Pandemics , Protein Binding , RNA, Viral/metabolism , RNA-Dependent RNA Polymerase/genetics , SARS-CoV-2/genetics , Saudi Arabia
20.
Molecules ; 27(19)2022 Sep 27.
Article in English | MEDLINE | ID: covidwho-2066276

ABSTRACT

The recent coronavirus disease (COVID-19) outbreak in Wuhan, China, has led to millions of infections and the death of approximately one million people. No targeted therapeutics are currently available, and only a few efficient treatment options are accessible. Many researchers are investigating active compounds from natural plant sources that may inhibit COVID-19 proliferation. Flavonoids are generally present in our diet, as well as traditional medicines and are effective against various diseases. Thus, here, we reviewed the potential of flavonoids against crucial proteins involved in the coronavirus infectious cycle. The fundamentals of coronaviruses, the structures of SARS-CoV-2, and the mechanism of its entry into the host's body have also been discussed. In silico studies have been successfully employed to study the interaction of flavonoids against COVID-19 Mpro, spike protein PLpro, and other interactive sites for its possible inhibition. Recent studies showed that many flavonoids such as hesperidin, amentoflavone, rutin, diosmin, apiin, and many other flavonoids have a higher affinity with Mpro and lower binding energy than currently used drugs such as hydroxylchloroquine, nelfinavir, ritonavir, and lopinavir. Thus, these compounds can be developed as specific therapeutic agents against COVID-19, but need further in vitro and in vivo studies to validate these compounds and pave the way for drug discovery.


Subject(s)
COVID-19 , Diosmin , Hesperidin , Antiviral Agents/chemistry , COVID-19/drug therapy , Flavonoids/chemistry , Flavonoids/pharmacology , Humans , Lopinavir/chemistry , Molecular Docking Simulation , Nelfinavir , Ritonavir/chemistry , Ritonavir/pharmacology , Rutin , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
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