scholarly journals Do fever-relieving medicines have anti-COVID activity: an in silico insight

2021 ◽  
Vol 16 (4) ◽  
pp. 293-300
Author(s):  
Fahad Hassan Shah ◽  
Kyeong Ho Lim ◽  
Song Ja Kim
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Active Site ◽  
Drug Repositioning ◽  
Receptor Binding Domain ◽  
Rna Dependent Rna Polymerase ◽  
Inhibitory Interaction ◽  
Essential Proteins ◽  
High Affinity ◽  
Main Protease ◽  
Anti Inflammatory

Aim: The present study was performed to determine the inhibitory interaction of fever-relieving medicines with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) essential proteins. Materials & methods: Structure-based drug repositioning was performed using PYRX 0.9 and these drugs were directed toward the predicted active site of SARS-CoV-2 spike glycoprotein receptor-binding domain, main protease and RNA-dependent RNA polymerase. Results: Results showed that acetaminophen and naproxen have considerable inhibitory activity and show a high affinity for active residues of these proteins. The prediction of activity spectra for substances (PASS) studies showed that these drugs are anti-inflammatory, antiviral and immunostimulant. Conclusion: Hence, it is proven that these drugs have antiviral activity against SARS-CoV-2 and can stimulate the immune and anti-inflammatory response against this disease.

scholarly journals Vitamin D and lumisterol novel metabolites can inhibit SARS-COV-2 replication machinery enzymes

2021 ◽  
Author(s):  
Shariq Qayyum ◽  
Taj Mohammad ◽  
Radomir M. Slominski ◽  
Md Imtaiyaz Hassan ◽  
Robert Tuckey ◽  
...  
Keyword(s):  
Vitamin D ◽  
Active Sites ◽  
Binding Affinities ◽  
Replication Machinery ◽  
Rna Dependent Rna Polymerase ◽  
High Affinity ◽  
Binding Partners ◽  
Novel Approach ◽  
Main Protease ◽  
Activity Measurements

Vitamin D deficiency significantly correlates with the severity of SARS-COV-2 infection. Molecular docking-based virtual screening studies predict that novel vitamin D and related lumisterol hydroxymetabolites are able to bind to the active sites of two SARS-COV-2 transcription machinery enzymes with high affinity. These enzymes are the main protease (Mpro) and RNA dependent RNA polymerase (RdRP) which play important roles in viral replication and establishing infection. Based on predicted binding affinities and specific interactions, we identified ten D3 and lumisterol analogs as likely binding partners of SARS-CoV-2 Mpro and RdRP and therefore tested their ability to inhibit these enzymes. Activity measurements demonstrated that 25(OH)L3, 24(OH)L3 and 20(OH)7DHC are the most effective of the hydroxymetabolites tested at inhibiting the activity of SARS-CoV-2 Mpro, causing 10-19% inhibition. These same derivatives as well as other hydroxylumisterols and hydroxyvitamin D3 metabolites inhibited RdRP by 50-60%. Thus, inhibition of these enzymes by vitamin D and lumisterol metabolites may provide a novel approach to hindering the SARS-COV-2 infection.

scholarly journals Pathology and pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

2020 ◽  
Vol 245 (15) ◽  
pp. 1299-1307
Author(s):  
Henok Kessete Afewerky
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Indirect Effects ◽  
Clinical Characteristics ◽  
Receptor Binding Domain ◽  
Structural Studies ◽  
Direct And Indirect Effects ◽  
Basic Information ◽  
Angiotensin Converting Enzyme 2 ◽  
High Affinity ◽  
Current Survey

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a beta coronavirus that causes infectious respiratory disease, named as coronavirus disease of 2019 (COVID-19). While extensive studies have provided basic information on clinical characteristics of COVID-19, the disease pathology is not fully known. The SARS-CoV-2 virus structural studies and biochemical experiments have also indicated that the virus receptor-binding domain (RBD) binds with a high affinity to angiotensin-converting enzyme-2 (ACE-2) receptor from humans; however, the mechanism remains unclear. Hereunder, a summary of relevant findings in the SARS-CoV-2 virus pathology and major pathogenicity mechanisms are discussed. This review of studies provides additional enlightenments on the way forward to prevent further spread or even cure for the SARS-CoV-2 virus-caused COVID-19 disease, either-or should a similar viral plague occur in the future. Impact statement The current survey of studies outlines the direct and indirect effects of SARS-CoV-2 on the specific body systems and summarizes the SARS-CoV-2 main pathogenicity mechanisms that require attention during patient hospitalization and for further research.

scholarly journals Efficacy of natural compounds from Tinospora cordifolia against SARS-CoV-2 protease, surface glycoprotein and RNA polymerase.

2020 ◽  
Author(s):  
Vasanthkumar Sagar ◽  
Arun HS Kumar
Keyword(s):  
Rna Polymerase ◽  
Host Cell ◽  
Natural Compounds ◽  
Surface Glycoprotein ◽  
Tinospora Cordifolia ◽  
Receptor Binding Domain ◽  
Rna Dependent Rna Polymerase ◽  
Virus Attachment ◽  
High Binding ◽  
Main Protease

Abstract Background: Antiviral activity of natural compounds from Tinospora cordifolia (Amritaballi) were evaluated for their efficacy against SARS-CoV-2 targets involved in virus attachment and replication. Materials and Methods: The binding efficacy (binding affinity, Ki and IC50 values) of natural compounds from Tinospora cordifolia were tested using Insilco tools against four key SARS-CoV-2 targets i.e., 1) surface glycoprotein (6VSB) and 2) Receptor binding domain (6M0J) both responsible for attachment of the virus to host cell, 3) RNA dependent RNA polymerase (6M71) and 4) main protease (6Y84) responsible for replication of the virus in the host cell. Results: Berberine, Isocolumbin, Magnoflorine and Tinocordiside showed high binding efficacy against all the four key SARS-CoV-2 targets. Tinocordiside and Isocolumbin showed IC50 value of < 1 µM against both 6Y84 and 6VSB. Conclusion: At least four natural compounds from Tinospora cordifolia showed high binding efficacy against SARS-CoV-2 targets involved in attachment and replication of the virus. Hence validating the merit of using Tinospora cordifolia in the clinical management of infection caused by SARS-CoV-2.

A New Lead for Nonpeptidic Active-Site-Directed Inhibitors of the Severe Acute Respiratory Syndrome Coronavirus Main Protease Discovered by a Combination of Screening and Docking Methods‖

2005 ◽  
Vol 48 (22) ◽  
pp. 6832-6842 ◽  
Author(s):  
Ulrich Kaeppler ◽  
Nikolaus Stiefl ◽  
Markus Schiller ◽  
Radim Vicik ◽  
Alexander Breuning ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Active Site ◽  
Main Protease

scholarly journals Phenothiazines as dual inhibitors of SARS-CoV-2 main protease and COVID-19 inflammation

2021 ◽  
Author(s):  
Katrina L Forrestall ◽  
Darcy E Burley ◽  
Meghan Kirsten Cash ◽  
Ian Pottie ◽  
Sultan Darvesh
Keyword(s):  
Viral Replication ◽  
Active Site ◽  
Acute Infection ◽  
Binding Energies ◽  
Neurotransmitter Receptors ◽  
Main Protease ◽  
Dual Action ◽  
Inhibition Constants ◽  
Anti Inflammatory ◽  
Essential Enzyme

COVID-19, caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) currently has no treatment for acute infection. The main protease (Mpro) of SARS-CoV-2 is an essential enzyme for viral replication and an attractive target for disease intervention. The phenothiazine moiety has demonstrated drug versatility for biological systems, including inhibition of butyrylcholinesterase, a property important in the cholinesterase anti-inflammatory cascade. Nineteen phenothiazine drugs were investigated using in silico modelling techniques to predict binding energies and inhibition constants (Ki values) with SARS-CoV-2 Mpro. Since most side-effects of phenothiazines are due to interactions with various neurotransmitter receptors and transporters, phenothiazines with few such interactions were also investigated. All compounds were found to bind to the active site of SARS-CoV-2 Mpro and showed Ki values ranging from 1.30 to 52.4 µM. Nine phenothiazines showed inhibition constants <10 µM. The compounds with limited interactions with neurotransmitter receptors and transporters showed micromolar (µM) Ki values. Docking results were compared with remdesivir and showed similar interactions with key residues Glu-166 and Gln-189 in the active site. This work has identified several phenothiazines with limited neurotransmitter receptor and transporter interactions and that may provide the dual action of inhibiting SARS-CoV-2 Mpro to prevent viral replication and promote the release of anti-inflammatory cytokines to curb viral-induced inflammation. These compounds are promising candidates for further investigation against SARS-CoV-2.

scholarly journals FDA-Approved Drugs with Potent In Vitro Antiviral Activity against Severe Acute Respiratory Syndrome Coronavirus 2

2020 ◽  
Vol 13 (12) ◽  
pp. 443
Author(s):  
Ahmed Mostafa ◽  
Ahmed Kandeil ◽  
Yaseen A. M. M. Elshaier ◽  
Omnia Kutkat ◽  
Yassmin Moatasim ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Antiviral Activity ◽  
Drug Repositioning ◽  
Data Bank ◽  
Binding Mode ◽  
Therapeutic Benefits ◽  
Anti Inflammatory ◽  
Approved Drugs ◽  
Fda Approved Drugs

(1) Background: Drug repositioning is an unconventional drug discovery approach to explore new therapeutic benefits of existing drugs. Currently, it emerges as a rapid avenue to alleviate the COVID-19 pandemic disease. (2) Methods: Herein, we tested the antiviral activity of anti-microbial and anti-inflammatory Food and Drug Administration (FDA)-approved drugs, commonly prescribed to relieve respiratory symptoms, against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the viral causative agent of the COVID-19 pandemic. (3) Results: Of these FDA-approved antimicrobial drugs, Azithromycin, Niclosamide, and Nitazoxanide showed a promising ability to hinder the replication of a SARS-CoV-2 isolate, with IC50 of 0.32, 0.16, and 1.29 µM, respectively. We provided evidence that several antihistamine and anti-inflammatory drugs could partially reduce SARS-CoV-2 replication in vitro. Furthermore, this study showed that Azithromycin can selectively impair SARS-CoV-2 replication, but not the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). A virtual screening study illustrated that Azithromycin, Niclosamide, and Nitazoxanide bind to the main protease of SARS-CoV-2 (Protein data bank (PDB) ID: 6lu7) in binding mode similar to the reported co-crystalized ligand. Also, Niclosamide displayed hydrogen bond (HB) interaction with the key peptide moiety GLN: 493A of the spike glycoprotein active site. (4) Conclusions: The results suggest that Piroxicam should be prescribed in combination with Azithromycin for COVID-19 patients.

scholarly journals A Survey of Inhibitors for the Main Protease of Coronaviruses with the Potential for Development of Broad-Spectrum Therapeutics

2021 ◽  
Vol 17 (4) ◽  
pp. 71-84
Author(s):  
Alyssa Sanders ◽  
Samuel Ricci ◽  
Sarah Uribe ◽  
Bridget Boyle ◽  
Brian Nepper ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Viral Replication ◽  
Broad Spectrum ◽  
Active Site ◽  
Human Life ◽  
Neuraminidase Inhibitor ◽  
Main Protease ◽  
The World ◽  
Potential Inhibitors

The coronaviruses plaguing humanity in the 21st century share much in common: a spontaneous route of origin from wild animals, a propensity to take human life, and, importantly, a highly conserved set of biological machinery necessary for viral replication. Most recently, the SARS-CoV-2 is decimating economies around the world and has claimed over two million human lives, reminding the world of a need for an effective drug against present and future coronaviruses. To date, attempts to repurpose clinically approved antiviral medications show minimal promise, highlighting the need for development of new antiviral drugs. Nucleotide analog inhibitors are a promising therapeutic candidate, but early data from clinical studies suggests these compounds have limited efficacy. However, novel compounds targeting the main protease responsible for critical steps in viral assembly are gaining considerable interest because they offer the potential for broad-spectrum coronavirus therapy. Here, we review the literature regarding potential inhibitors for the main protease of coronaviruses, especially SARS-CoV-2, analyze receptor-drug interactions, and draw conclusions about candidate inhibitors for future outbreaks. Promising candidates for development of a broad-spectrum coronavirus protease inhibitor include the neuraminidase inhibitor 3K, the peptidomimetic inhibitor 11a and 11b, the α-ketoamide inhibitor 13b, the aldehyde prodrug, and the phosphate prodrug developed by Pfizer. In silico and in vitro analyses have shown that these inhibitors strongly interact with the active site of the main protease, and to varying degrees, prevent viral replication via interactions with the largely conserved active site pockets. KEYWORDS: Severe Acute Respiratory Syndrome Coronavirus; Middle East Respiratory Syndrome Coronavirus; Severe Acute Respiratory Syndrome Coronavirus 2; Replicase Polypeptide; Protease; Neuraminidase Inhibitor; Peptidomimetic Inhibitor; α-Ketoamide Inhibitor; Molecular Docking

scholarly journals Potential of amentoflavone with antiviral properties in COVID-19 treatment

2021 ◽  
Vol 15 (4) ◽  
pp. 153-159
Author(s):  
Akhilesh Vikram Singh
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Therapeutic Potential ◽  
Active Agent ◽  
Docking Studies ◽  
Herbal Extracts ◽  
Traditional Medicines ◽  
Preventive Actions ◽  
Main Protease ◽  
Anti Inflammatory ◽  
Antiviral Medications

Abstract Amentoflavone is one of the flavonoids that are known for their antiviral effects and many of them are predicted to have inhibitory effects against severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome Coronavirus (MERS-CoV) enzymes 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro). Amentoflavone is a biflavonoid found in the herbal extracts of St. John's wort (Hypericum perforatum), Gingko biloba, Selaginella tamariscina, Torreya nucifera, and many other plants. Its pharmacological actions have been listed as antiviral, antibacterial, antioxidant, anti-inflammatory, antidiabetic, antidepressant, and neuroprotective. Molecular docking studies have found that amentoflavone binds strongly to the active site of the main protease (Mpro) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As conventional antiviral medications are met with limited success against coronavirus disease-2019 (COVID-19) and vaccines are one of the only weapons against COVID-19 in the pharmaceutical armamentarium, traditional medicines are being considered for the forefront battle against COVID-19. Clinical studies with Hypericum and Gingko extract as additional or alternative drugs/supplements are registered. Here we review the potential of amentoflavone, an active agent in both Hypericum and Gingko extract as an adjunct therapy for COVID-19. Its anti-inflammatory, antioxidant, and sepsis preventive actions could provide protection against the “cytokine storm.” Compared with the herbal extracts, which induce cytochrome P450 (CYP) and uridine 5′-diphospho (UDP)-glucuronosyltransferases (UGT) activity producing a negative herb–drug interaction, amentoflavone is a potent inhibitor of CYP3A4, CYP2C9, and UGT. Further studies into the therapeutic potential of amentoflavone against the coronavirus infection are warranted.

scholarly journals Deciphering the Binding Mechanism of Dexamethasone Against SARS-CoV-2 Main Protease: Computational Molecular Modelling Approach

2020 ◽  
Author(s):  
Shafi Ullah Khan ◽  
Thet.thet Htar
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bonds ◽  
Active Site ◽  
Binding Mechanism ◽  
Protein Targets ◽  
High Affinity ◽  
Main Protease ◽  
Dynamics Simulations ◽  
Covalent Inhibitor ◽  
Modelling Approach

<p>At present, there are no proven agents for the treatment of 2019 coronavirus disease (COVID-19). The available evidence has not allowed guidelines to clearly recommend any drugs outside the context of clinical trials. One of the most important SARS-CoV-2 protein targets for therapeutics is the 3C-like protease (main protease, Mpro). Here in this study we utilize the recently published 6W63 crystal structure of Mpro complexed with a non-covalent inhibitor X77. Various docking methods FRED, HYBRID, CDOCKER and LEADFINDER tools were benchmark to optimally re-dock the co-crystal ligand within the active site of SARS-COV-2 Mpro. This study was restricted to molecular docking without validation by molecular dynamics simulations. CDOCKER was found to depict the exact binding of co-crystal ligand having lowest RMSD of less than 2 A. Interactions with the SARS-COV-2 Mpro may play a key role in fighting against viruses. Dexamethasone was found to bind with a high affinity to the same sites of the SARS-COV-2 Mpro than the Remdesivir. Dexamethasone was forming six hydrogen bonds compared to the three hydrogen bonds formed by Remdesivir within the active site of SARS-COV-2 Mpro. LEU141, GLY143, HIS163, GLU166, GLN192 were the key amino acid residue of SAR-COV-2 Mpro involved in stabilizing the complex between Dexamethasone and SARS-COV-2 Mpro. The results suggest the effectiveness of Dexamethasone as potent drugs against SARS-CoV-2 since it bind tightly to its Mpro. In addition, the results also suggest that dexamethasone as top antiviral treatments option than the Remdesivir with high potential to fight the SARS-CoV-2.</p>

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