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1.
J Mol Model ; 28(4): 82, 2022 Mar 05.
Article in English | MEDLINE | ID: covidwho-1729317

ABSTRACT

Novel SARS coronavirus or SARS-CoV-2 is a novel coronavirus that was identified and spread from Wuhan in 2019. On January 30th, the World Health Organization declared the coronavirus outbreak as a Global Public Health Emergency. Although Remdesivir and Molnupiravir are FDA-approved drugs for COVID-19, finding new efficient and low-cost antiviral drugs against COVID-19 for applying in more countries can still be helpful. One of the potential sources for finding new and low-cost drugs is the herbal compounds in addition to repurposing FDA-approved drugs. So, in this study, we focused on finding effective drug candidates against COVID-19 based on the computational approaches. As ACE2 serves as a critical receptor for cell entry of this virus. Inhibiting the binding site of SARS-CoV-2 on human ACE2 provides a promising therapeutic approach for developing drugs against SARS-CoV-2. Herein, we applied a bioinformatics approach to identify possible potential inhibitors of SARS-CoV-2. A library of FDA-approved compounds and five natural compounds was screened using Smina docking. Top-docking compounds are then applied in Molecular Dynamics (MD) simulation to assess the stability of ACE2-inhibitor complexes. Results indicate that Luteolin and Chrysin represent high conformation stability with ACE2 during 120 ns of Molecular Dynamics simulation. The binding free energies of Luteolin and Chrysin were calculated by the Molecular Mechanics/Poisson-Boltzmann Surface Area method (MM/PBSA) which confirmed the relative binding free energy of these drugs to ACE2 in favor of the effective binding. So, Luteolin and Chrysin could sufficiently interact with ACE2 and block the Spike binding pocket of ACE2 and can be a potential inhibitor against the binding of SARS-CoV-2 to ACE2 receptor which is an early stage of infection. Luteolin and Chrysin could be suggestive as beneficial compounds for preventing or reducing SARS-CoV-2 transmission and infection which need experimental work to prove.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/prevention & control , Flavonoids/pharmacology , Luteolin/pharmacology , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/metabolism , COVID-19/transmission , Drug Repositioning , Flavonoids/therapeutic use , Humans , Luteolin/therapeutic use , Molecular Dynamics Simulation , Protein Binding
2.
Front Endocrinol (Lausanne) ; 12: 802447, 2021.
Article in English | MEDLINE | ID: covidwho-1699427

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a serious epidemic, characterized by potential mutation and can bring about poor vaccine efficiency. It is evidenced that patients with malignancies, including prostate cancer (PC), may be highly vulnerable to the SARS-CoV-2 infection. Currently, there are no existing drugs that can cure PC and COVID-19. Luteolin can potentially be employed for COVID-19 treatment and serve as a potent anticancer agent. Our present study was conducted to discover the possible drug target and curative mechanism of luteolin to serve as treatment for PC and COVID-19. The differential gene expression of PC cases was determined via RNA sequencing. The application of network pharmacology and molecular docking aimed to exhibit the drug targets and pharmacological mechanisms of luteolin. In this study, we found the top 20 up- and downregulated gene expressions in PC patients. Enrichment data demonstrated anti-inflammatory effects, where improvement of metabolism and enhancement of immunity were the main functions and mechanism of luteolin in treating PC and COVID-19, characterized by associated signaling pathways. Additional core drug targets, including MPO and FOS genes, were computationally identified accordingly. In conclusion, luteolin may be a promising treatment for PC and COVID-19 based on bioinformatics findings, prior to future clinical validation and application.


Subject(s)
COVID-19/drug therapy , Drug Discovery/methods , Luteolin/therapeutic use , Prostatic Neoplasms/drug therapy , COVID-19/pathology , Computational Biology/methods , High-Throughput Screening Assays/methods , Humans , Luteolin/pharmacology , Male , Metabolic Networks and Pathways/drug effects , Models, Molecular , Molecular Docking Simulation , Molecular Targeted Therapy/methods , Prostatic Neoplasms/pathology , Protein Interaction Maps/drug effects , Protein Interaction Maps/physiology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
3.
Med Sci Monit ; 28: e934102, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1651076

ABSTRACT

BACKGROUND Heat-clearing and detoxifying herbs (HDHs) play an important role in the prevention and treatment of coronavirus infection. However, their mechanism of action needs further study. This study aimed to explore the anti-coronavirus basis and mechanism of HDHs. MATERIAL AND METHODS Database mining was performed on 7 HDHs. Core ingredients and targets were screened according to ADME rules combined with Neighborhood, Co-occurrence, Co-expression, and other algorithms. GO enrichment and KEGG pathway analyses were performed using the R language. Finally, high-throughput molecular docking was used for verification. RESULTS HDHs mainly acts on NOS3, EGFR, IL-6, MAPK8, PTGS2, MAPK14, NFKB1, and CASP3 through quercetin, luteolin, wogonin, indirubin alkaloids, ß-sitosterol, and isolariciresinol. These targets are mainly involved in the regulation of biological processes such as inflammation, activation of MAPK activity, and positive regulation of NF-kappaB transcription factor activity. Pathway analysis further revealed that the pathways regulated by these targets mainly include: signaling pathways related to viral and bacterial infections such as tuberculosis, influenza A, Ras signaling pathways; inflammation-related pathways such as the TLR, TNF, MAPK, and HIF-1 signaling pathways; and immune-related pathways such as NOD receptor signaling pathways. These pathways play a synergistic role in inhibiting lung inflammation and regulating immunity and antiviral activity. CONCLUSIONS HDHs play a role in the treatment of coronavirus infection by regulating the body's immunity, fighting inflammation, and antiviral activities, suggesting a molecular basis and new strategies for the treatment of COVID-19 and a foundation for the screening of new antiviral drugs.


Subject(s)
COVID-19/drug therapy , Coronavirus/drug effects , Drugs, Chinese Herbal/pharmacology , SARS-CoV-2/drug effects , Alkaloids/chemistry , Alkaloids/pharmacology , Caspase 3/drug effects , Caspase 3/genetics , Coronavirus/metabolism , Coronavirus Infections/drug therapy , Cyclooxygenase 2/drug effects , Cyclooxygenase 2/genetics , Databases, Pharmaceutical , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/therapeutic use , Flavanones/chemistry , Flavanones/pharmacology , Humans , Indoles/chemistry , Indoles/pharmacology , Interleukin-6/genetics , Lignin/chemistry , Lignin/pharmacology , Luteolin/chemistry , Luteolin/pharmacology , Mitogen-Activated Protein Kinase 14/drug effects , Mitogen-Activated Protein Kinase 14/genetics , Mitogen-Activated Protein Kinase 8/drug effects , Mitogen-Activated Protein Kinase 8/genetics , Molecular Docking Simulation , NF-kappa B p50 Subunit/drug effects , NF-kappa B p50 Subunit/genetics , Naphthols/chemistry , Naphthols/pharmacology , Nitric Oxide Synthase Type III/drug effects , Nitric Oxide Synthase Type III/genetics , Protein Interaction Maps , Quercetin/chemistry , Quercetin/pharmacology , SARS-CoV-2/metabolism , Signal Transduction , Sitosterols/chemistry , Sitosterols/pharmacology , Transcriptome/drug effects , Transcriptome/genetics
5.
Aging (Albany NY) ; 13(21): 23913-23935, 2021 11 03.
Article in English | MEDLINE | ID: covidwho-1502964

ABSTRACT

LianHuaQingWen (LHQW) improves clinical symptoms and alleviates the severity of COVID-19, but the mechanism is unclear. This study aimed to investigate the potential molecular targets and mechanisms of LHQW in treating COVID-19 using a network pharmacology-based approach and molecular docking analysis. The main active ingredients, therapeutic targets of LHQW, and the pathogenic targets of COVID-19 were screened using the TCMSP, UniProt, STRING, and GeneCards databases. According to the "Drug-Ingredients-Targets-Disease" network, Interleukin 6 (IL6) was identified as the core target, and quercetin, luteolin, and wogonin as the active ingredients of LHQW associated with IL6. The response to lipopolysaccharide was the most significant biological process identified by gene ontology enrichment analysis, and AGE-RAGE signaling pathway activation was prominent based on the interaction between LHQW and COVID-19. Protein-protein docking analysis showed that IL6 receptor (IL6R)/IL6/IL6 receptor subunit beta (IL6ST) and Spike protein were mainly bound via conventional hydrogen bonds. Furthermore, protein-small molecule docking showed that all three active ingredients could bind stably in the binding model of IL6R/IL6 and IL6ST. Our findings suggest that LHQW may inhibit the lipopolysaccharide-mediated inflammatory response and regulate the AGE-RAGE signaling pathway through IL6. In addition, the N-terminal domain of the S protein of COVID-19 has a good binding activity to IL6ST, and quercetin and wogonin in LHQW may affect IL6ST-mediated IL6 signal transduction and a large number of signaling pathways downstream to other cytokines by directly affecting protein-protein interaction. These findings suggest the potential molecular mechanism by which LHQW inhibits COVID-19 through the regulation of IL6R/IL6/IL6ST.


Subject(s)
COVID-19 , Drugs, Chinese Herbal/pharmacology , Glycation End Products, Advanced/metabolism , Interleukin-6/metabolism , Receptor for Advanced Glycation End Products/metabolism , SARS-CoV-2 , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Cytokine Receptor gp130/metabolism , Flavanones/pharmacology , Humans , Luteolin/pharmacology , Molecular Docking Simulation , Quercetin/pharmacology , Receptors, Interleukin-6/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Signal Transduction/drug effects , Signal Transduction/immunology , Spike Glycoprotein, Coronavirus/metabolism
6.
J Mol Model ; 27(8): 221, 2021 Jul 08.
Article in English | MEDLINE | ID: covidwho-1300483

ABSTRACT

Natural products have served human life as medications for centuries. During the outbreak of COVID-19, a number of naturally derived compounds and extracts have been tested or used as potential remedies against COVID-19. Tetradenia riparia extract is one of the plant extracts that have been deployed and claimed to manage and control COVID-19 by some communities in Tanzania and other African countries. The active compounds isolated from T. riparia are known to possess various biological properties including antimalarial and antiviral. However, the underlying mechanism of the active compounds against SARS-CoV-2 remains unknown. Results in the present work have been interpreted from the view point of computational methods including molecular dynamics, free energy methods, and metadynamics to establish the related mechanism of action. Among the constituents of T. riparia studied, luteolin inhibited viral cell entry and was thermodynamically stable. The title compound exhibit residence time and unbinding kinetics of 68.86 ms and 0.014 /ms, respectively. The findings suggest that luteolin could be potent blocker of SARS-CoV-2 cell entry. The study shades lights towards identification of bioactive constituents from T. riparia against COVID-19, and thus bioassay can be carried out to further validate such observations.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Luteolin/pharmacology , Molecular Dynamics Simulation , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Virus Internalization/drug effects , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/isolation & purification , Antiviral Agents/metabolism , Binding Sites , COVID-19/virology , Host-Pathogen Interactions , Humans , Kinetics , Lamiaceae/chemistry , Luteolin/isolation & purification , Luteolin/metabolism , Plant Extracts/isolation & purification , Plant Extracts/metabolism , Protein Binding , Protein Conformation , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/metabolism
7.
Biofactors ; 47(2): 242-244, 2021 03.
Article in English | MEDLINE | ID: covidwho-1212723
9.
Biosci Rep ; 41(1)2021 01 29.
Article in English | MEDLINE | ID: covidwho-1043444

ABSTRACT

OBJECTIVE: ´Three formulas and three medicines,' namely, Jinhua Qinggan Granule, Lianhua Qingwen Capsule, Xuebijing Injection, Qingfei Paidu Decoction, HuaShi BaiDu Formula, and XuanFei BaiDu Granule, were proven to be effective for coronavirus disease 2019 (COVID-19) treatment. The present study aimed to identify the active chemical constituents of this traditional Chinese medicine (TCM) and investigate their mechanisms through interleukin-6 (IL-6) integrating network pharmacological approaches. METHODS: We collected the compounds from all herbal ingredients of the previously mentioned TCM, but those that could down-regulate IL-6 were screened through the network pharmacology approach. Then, we modeled molecular docking to evaluate the binding affinity between compounds and IL-6. Furthermore, we analyzed the biological processes and pathways of compounds. Finally, we screened out the core genes of compounds through the construction of the protein-protein interaction network and the excavation of gene clusters of compounds. RESULTS: The network pharmacology research showed that TCM could decrease IL-6 using several compounds, such as quercetin, ursolic acid, luteolin, and rutin. Molecular docking results showed that the molecular binding affinity with IL-6 of all compounds except γ-aminobutyric acid was < -5.0 kJ/mol, indicating the potential of numerous active compounds in TCM to directly interact with IL-6, leading to an anti-inflammation effect. Finally, Cytoscape 3.7.2 was used to topologize the biological processes and pathways of compounds, revealing potential mechanisms for COVID-19 treatment. CONCLUSION: These results indicated the positive effect of TCM on the prevention and rehabilitation of COVID-19 in at-risk people. Quercetin, ursolic acid, luteolin, and rutin could inhibit COVID-19 by down-regulating IL-6.


Subject(s)
Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , Drugs, Chinese Herbal/pharmacology , Interleukin-6/immunology , Anti-Inflammatory Agents/chemistry , COVID-19/immunology , Drug Discovery , Drugs, Chinese Herbal/chemistry , Humans , Interleukin-6/antagonists & inhibitors , Luteolin/analysis , Luteolin/pharmacology , Medicine, Chinese Traditional , Molecular Docking Simulation , Protein Interaction Maps/drug effects , Quercetin/analysis , Quercetin/pharmacology , Rutin/analysis , Rutin/pharmacology , Triterpenes/analysis , Triterpenes/pharmacology
10.
Int J Antimicrob Agents ; 56(2): 106012, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-438396

ABSTRACT

In the current spread of novel coronavirus (SARS-CoV-2), antiviral drug discovery is of great importance. AutoDock Vina was used to screen potential drugs by molecular docking with the structural protein and non-structural protein sites of new coronavirus. Ribavirin, a common antiviral drug, remdesivir, chloroquine and luteolin were studied. Honeysuckle is generally believed to have antiviral effects in traditional Chinese medicine. In this study, luteolin (the main flavonoid in honeysuckle) was found to bind with a high affinity to the same sites of the main protease of SARS-CoV-2 as the control molecule. Chloroquine has been proved clinically effective and can bind to the main protease; this may be the antiviral mechanism of this drug. The study was restricted to molecular docking without validation by molecular dynamics simulations. Interactions with the main protease may play a key role in fighting against viruses. Luteolin is a potential antiviral molecule worthy of attention.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Chloroquine/pharmacology , Computational Biology , Coronavirus Infections/virology , Luteolin/pharmacology , Pneumonia, Viral/virology , Antiviral Agents/chemistry , COVID-19 , Chloroquine/metabolism , Humans , Luteolin/metabolism , Molecular Docking Simulation , Pandemics , SARS-CoV-2
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