Atazanavir Is a Competitive Inhibitor of SARS-CoV-2 Mpro, Impairing Variants Replication In Vitro and In Vivo

Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19), however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based, and in vivo assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that SARS-CoV-2 main protease (Mpro) was inhibited by ATV, with Morrison's inhibitory constant (Ki) 1.5-fold higher than boceprevir (GC376, a positive control). ATV was a competitive inhibition, increasing the Mpro's Michaelis-Menten (Km) more than 6-fold. Cell-based assays indicated that SARS-CoV-2 gamma is more susceptible to ATV than its predecessor strain B.1. Using oral administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed in the lung from infected and treated mice. Our studies may contribute to a better comprehension of the Mpro/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease.

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Identification of Potent Inhibitors of COVID-19 Main Protease Enzyme by Molecular Docking Study

10.26434/chemrxiv.12179202 ◽

2020 ◽

Author(s):

pooja singh ◽

Angkita Sharma ◽

Shoma Paul Nandi

Keyword(s):

Molecular Docking ◽

Antiviral Drug ◽

Cyclopiazonic Acid ◽

Docking Study ◽

Molecular Docking Study ◽

Docking Score ◽

Protease Enzyme ◽

Main Protease

Within the span of a few months, the severe acute respiratory syndrome coronavirus, COVID-19 (SARS-CoV-2), has proven to be a pandemic, affecting the world at an exponential rate. It is extremely pathogenic and causes communicable infection in humans. Viral infection causes difficulties in breathing, sore throat, cough, high fever, muscle pain, diarrhea, dyspnea, and may lead to death. Finding a proper drug and vaccines against this virus is the need of the hour. The RNA genome of COVID19 codes for the main protease Mpro, which is required for viral multiplication. To identify possible antiviral drug(s), we performed molecular docking studies. Our screen identified ten biomolecules naturally present in Aspergillus flavus and Aspergillus oryzae fungi. These molecules include Aspirochlorine, Aflatoxin B1, Alpha-Cyclopiazonic acid, Sporogen, Asperfuran, Aspergillomarasmine A, Maltoryzine, Kojic acid, Aflatrem and Ethyl 3-nitropropionic acid, arranged in the descending order of their docking score. Aspirochlorine exhibited the docking score of – 7.18 Kcal/mole, higher than presently used drug Chloroquine (-6.2930522 Kcal/mol) and out of ten ligands studied four has docking score higher than chloroquine. These natural bioactive compounds could be tested for their ability to inhibit viral growth in- vitro and in-vivo.

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Potential Bioactive glycosylated flavonoids as SARS-CoV-2 Main protease Inhibitors: A molecular Docking Study

10.31219/osf.io/k4h5f ◽

2020 ◽

Author(s):

sabri ahmed cherrak ◽

merzouk hafida ◽

mokhtari soulimane nassima

Keyword(s):

Molecular Docking ◽

Data Bank ◽

Docking Study ◽

Docking Studies ◽

Molecular Docking Study ◽

Chemical Structures ◽

In Vivo Experiments ◽

Main Protease

A novel (COVID-19) responsible of acute respiratory infection closely related to SARS-CoV has recently emerged. So far there is no consensus for drug treatment to stop the spread of the virus. Discovery of a drug that would limit the virus expansion is one of the biggest challenges faced by the humanity in the last decades. In this perspective, testing existing drugs as inhibitors of the main COVID-19 protease is a good approach.Among natural phenolic compounds found in plants, fruit, and vegetables; flavonoids are the most abundant. Flavonoids, especially in their glycosylated forms, display a number of physiological activities, which makes them interesting to investigate as antiviral molecules.The flavonoids chemical structures were downloaded from PubChem and protease structure 6lu7 was from the Protein Data Bank site. Molecular docking study was performed using AutoDock Vina. Among the tested molecules Quercetin-3-O-rhamnoside showed the highest binding affinity (-9,7 kcal/mol). Docking studies showed that glycosylated flavonoids are good inhibitors for the covid-19 protease and could be further investigated by in vitro and in vivo experiments for further validation.

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An Investigation into the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease Using Molecular Docking Study

10.26434/chemrxiv.12129513.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Sourav Das ◽

Sharat Sarmah ◽

Sona Lyndem ◽

Atanu Singha Roy

Keyword(s):

Clinical Trials ◽

Molecular Docking ◽

Active Site ◽

Natural Compound ◽

World Health ◽

Molecular Docking Study ◽

Control Drug ◽

Main Protease

A new strain of a novel infectious disease affecting millions of people, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently been declared as a pandemic by the World Health Organization (WHO). Currently, several clinical trials are underway to identify specific drugs for the treatment of this novel virus. The inhibition of the SARS-CoV-2 main protease is necessary for the blockage of the viral replication. Here, in this study, we have utilized a blind molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 main protease, by screening a total of 33 molecules which includes natural products, anti-virals, anti-fungals, anti-nematodes and anti-protozoals. All the studied molecules could bind to the active site of the SARS-CoV-2 protease (PDB: 6Y84), out of which rutin (a natural compound) has the highest inhibitor efficiency among the 33 molecules studied, followed by ritonavir (control drug), emetine (anti-protozoal), hesperidin (a natural compound), lopinavir (control drug) and indinavir (anti-viral drug). All the molecules, studied out here could bind near the crucial catalytic residues, HIS41 and CYS145 of the main protease, and the molecules were surrounded by other active site residues like MET49, GLY143, HIS163, HIS164, GLU166, PRO168, and GLN189. As this study is based on molecular docking, hence being particular about the results obtained, requires extensive wet-lab experimentation and clinical trials under in vitro as well as in vivo conditions.

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An Investigation into the Identification of Potential Inhibitors of SARS-CoV-2 Main Protease Using Molecular Docking Study

10.26434/chemrxiv.12129513 ◽

2020 ◽

Author(s):

Sourav Das ◽

Sharat Sarmah ◽

Sona Lyndem ◽

Atanu Singha Roy

Keyword(s):

Clinical Trials ◽

Molecular Docking ◽

Active Site ◽

Natural Compound ◽

World Health ◽

Molecular Docking Study ◽

Control Drug ◽

Main Protease

A new strain of a novel infectious disease affecting millions of people, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently been declared as a pandemic by the World Health Organization (WHO). Currently, several clinical trials are underway to identify specific drugs for the treatment of this novel virus. The inhibition of the SARS-CoV-2 main protease is necessary for the blockage of the viral replication. Here, in this study, we have utilized a blind molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 main protease, by screening a total of 33 molecules which includes natural products, anti-virals, anti-fungals, anti-nematodes and anti-protozoals. All the studied molecules could bind to the active site of the SARS-CoV-2 protease (PDB: 6Y84), out of which rutin (a natural compound) has the highest inhibitor efficiency among the 33 molecules studied, followed by ritonavir (control drug), emetine (anti-protozoal), hesperidin (a natural compound), lopinavir (control drug) and indinavir (anti-viral drug). All the molecules, studied out here could bind near the crucial catalytic residues, HIS41 and CYS145 of the main protease, and the molecules were surrounded by other active site residues like MET49, GLY143, HIS163, HIS164, GLU166, PRO168, and GLN189. As this study is based on molecular docking, hence being particular about the results obtained, requires extensive wet-lab experimentation and clinical trials under in vitro as well as in vivo conditions.

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Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro) Identified from the Library of FDA Approved Drugs Using Molecular Docking Studies

10.20944/preprints202004.0149.v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Dipesh Verma ◽

Srajan Kapoor ◽

Satyajeet Das ◽

Krishan Thakur

Keyword(s):

Molecular Docking ◽

Therapeutic Potential ◽

Docking Studies ◽

Antiviral Compound ◽

Molecular Docking Studies ◽

Main Protease ◽

Approved Drugs ◽

Fda Approved Drugs

Corona Virus Infectious Disease-2019 (COVID-19) outbreak originated recently at Wuhan, China in December 2019. It has already spread rapidly to more than 200 countries and has been declared a pandemic by WHO. It is caused by a beta-coronavirus named as SARS-CoV-2. There is no definitive cure, either drug or vaccine, to treat or prevent this viral disease. Recently, the crystal structure of the main protease Mpro has been determined. Mpro is responsible for the proteolytic maturation of the polyprotein essential for the viral replication and transcription, which makes it an important drug target. The discovery of new drug molecules may take years before getting to the clinics. So, considering urgency we performed molecular docking studies using FDA approved drugs to identify molecules that could potentially bind to the substrate-binding site and inhibit SARS-CoV-2 main protease (Mpro). We used the Glide module in Schrodinger software suite to perform molecular docking studies followed by MM-GBSA based energy calculations to score the hit molecules. Molecular docking and manual analysis suggest that several drugs may bind and potentially inhibit Mpro. We also performed molecular simulations studies for selected compounds to evaluate protein-drug interactions. Interestingly, we observed only one antiviral compound, Adefovir, in the top50 list of compounds. Considering bioavailability, lesser toxicity, route of administration some of the top-ranked drugs including lumefantrine (antimalarial), dipyridamole (coronary vasodilator), dihydroergotamine (used for treating migraine), hexoprenaline (anti- asthmatic), riboflavin (vitamin B2) and pantethine (vitamin B5) may be taken forward for further in vitro and in vivo experiments to investigate their therapeutic potential.

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Phytochemicals of Rhus spp. as Potential Inhibitors of the SARS-CoV-2 Main Protease: Molecular Docking and Drug-Likeness Study

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/8814890 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Yousery E. Sherif ◽

Sami A. Gabr ◽

Nasser M. Hosny ◽

Ahmad H. Alghadir ◽

Rayan Alansari

Keyword(s):

Molecular Docking ◽

Specific Treatment ◽

Polyphenolic Compounds ◽

Protease Enzyme ◽

Main Protease ◽

Synthetic Accessibility ◽

Novel Coronavirus ◽

Potential Inhibitors

Background. The outbreak of coronavirus disease 2019 (COVID-19) induced by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in China and spread to cover the entire world with an ongoing pandemic. The magnitude of the situation and the fast spread of the new and deadly virus, as well as the lack of specific treatment, led to a focus on research to discover new therapeutic agents. Aim. In this study, we explore the potential inhibitory effects of some active polyphenolic constituents of Rhus spp. (sumac) against the SARS-CoV-2 main protease enzyme (Mpro; 6LU7). Methods. 26 active polyphenolic compounds of Rhus spp. were studied for their antiviral activity by molecular docking, drug likeness, and synthetic accessibility score (SAS) as inhibitors against the SARS-CoV-2 Mpro. Results. The results show that all tested compounds of sumac provided good interaction with the main active site of SARS-CoV-2 Mpro, with better, lower molecular docking energy (kcal/mol) compared to the well-known drugs chloroquine and favipiravir (Avigan). Only six active polyphenolic compounds of Rhus spp. (sumac), methyl 3,4,5-trihydroxybenzoate, (Z)-1-(2,4-dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)-2-hydroxyprop-2-en-1-one, (Z)-2-(3,4-dihydroxybenzylidene)-6-hydroxybenzofuran-3(2H)-one, 3,5,7-trihydroxy-2-(4-hydroxyphenyl)chroman-4-one, 2-(3,4-dihydroxyphenyl)-3,5-dihydroxy-7-methoxy-4H-chroman-4-one, and 3,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, were proposed by drug likeness, solubility in water, and SAS analysis as potential inhibitors of Mpro that may be used for the treatment of COVID-19. Conclusion. Six phenolic compounds of Rhus spp. are proposed for synthesis as potential inhibitors against Mpro and have potential for the treatment of COVID-19. These results encourage further in vitro and in vivo investigations of the proposed ligands and research on the preventive use of Rhus spp. against SARS-CoV-2.

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Identification of Potent Inhibitors of COVID-19 Main Protease Enzyme by Molecular Docking Study

10.26434/chemrxiv.12179202.v1 ◽

2020 ◽

Author(s):

pooja singh ◽

Angkita Sharma ◽

Shoma Paul Nandi

Keyword(s):

Molecular Docking ◽

Antiviral Drug ◽

Cyclopiazonic Acid ◽

Docking Study ◽

Molecular Docking Study ◽

Docking Score ◽

Protease Enzyme ◽

Main Protease

Within the span of a few months, the severe acute respiratory syndrome coronavirus, COVID-19 (SARS-CoV-2), has proven to be a pandemic, affecting the world at an exponential rate. It is extremely pathogenic and causes communicable infection in humans. Viral infection causes difficulties in breathing, sore throat, cough, high fever, muscle pain, diarrhea, dyspnea, and may lead to death. Finding a proper drug and vaccines against this virus is the need of the hour. The RNA genome of COVID19 codes for the main protease Mpro, which is required for viral multiplication. To identify possible antiviral drug(s), we performed molecular docking studies. Our screen identified ten biomolecules naturally present in Aspergillus flavus and Aspergillus oryzae fungi. These molecules include Aspirochlorine, Aflatoxin B1, Alpha-Cyclopiazonic acid, Sporogen, Asperfuran, Aspergillomarasmine A, Maltoryzine, Kojic acid, Aflatrem and Ethyl 3-nitropropionic acid, arranged in the descending order of their docking score. Aspirochlorine exhibited the docking score of – 7.18 Kcal/mole, higher than presently used drug Chloroquine (-6.2930522 Kcal/mol) and out of ten ligands studied four has docking score higher than chloroquine. These natural bioactive compounds could be tested for their ability to inhibit viral growth in- vitro and in-vivo.

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Tea flavonoids blocking multiple SARS-CoV-2 protein targets judged from molecular docking

10.21203/rs.3.rs-122589/v1 ◽

2020 ◽

Author(s):

Lufei Wang ◽

Siyao Sang ◽

Mingjie Su ◽

Simin Wang ◽

Hui Li

Keyword(s):

Molecular Docking ◽

Severe Acute Respiratory Syndrome ◽

Molecular Mechanisms ◽

Positive Control ◽

Potential Candidate ◽

Protein Targets ◽

Angiotensin Converting Enzyme 2 ◽

Patent Medicines ◽

Main Protease ◽

Chinese Patent

Abstract Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. Flavonoids derived Chinese patent medicines has outstanding curative effects for the improvement and treatment of COVID-19. There are numerous studies suggesting that flavonoids-rich tea have antiviral effects. However, bioactive compounds from tea flavonoids with anti-COVID-19 effect, and the potential molecular mechanisms are unclear. In this study, we performed a molecular docking of 468 tea flavonoids and its derivatives with main protease (Mpro), angiotensin-converting enzyme 2 (ACE2), RNA dependent RNA polymerase (RdRp), compared with the positive control drugs of each target. The results suggested that ACE2 and RdRp are the main targets inhibited by tea flavonoids.Q3G Isovitexin, and TF would be considered as the potential candidate compounds of RdRp and ACE2. Our study provides a theoretical basis for further drug design of anti-COVID-19.

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Action of Thioglycosides of 1,2,4-Triazoles and Imidazoles on the Oxidative Stress and Glycosidases in Mice with Molecular Docking

Letters in Drug Design & Discovery ◽

10.2174/1573413715666181212150955 ◽

2019 ◽

Vol 16 (6) ◽

pp. 696-710

Author(s):

Mahmoud Balbaa ◽

Doaa Awad ◽

Ahmad Abd Elaal ◽

Shimaa Mahsoub ◽

Mayssaa Moharram ◽

...

Keyword(s):

Oxidative Stress ◽

Molecular Docking ◽

Active Sites ◽

Biological Activities ◽

Imidazole Ring ◽

Quantitative Structure Activity Relationship ◽

Binding Interaction ◽

Qsar Study

Background: ,2,3-Triazoles and imidazoles are important five-membered heterocyclic scaffolds due to their extensive biological activities. These products have been an area of growing interest to many researchers around the world because of their enormous pharmaceutical scope. Methods: The in vivo and in vitro enzyme inhibition of some thioglycosides encompassing 1,2,4- triazole N1, N2, and N3 and/or imidazole moieties N4, N5, and N6. The effect on the antioxidant enzymes (superoxide dismutase, glutathione S-transferase, glutathione peroxidase and catalase) was investigated as well as their effect on α-glucosidase and β-glucuronidase. Molecular docking studies were carried out to investigate the mode of the binding interaction of the compounds with α- glucosidase and β -glucuronidase. In addition, quantitative structure-activity relationship (QSAR) investigation was applied to find out the correlation between toxicity and physicochemical properties. Results: The decrease of the antioxidant status was revealed by the in vivo effect of the tested compounds. Furthermore, the in vivo and in vitro inhibitory effects of the tested compounds were clearly pronounced on α-glucosidase, but not β-glucuronidase. The IC50 and Ki values revealed that the thioglycoside - based 1,2,4-triazole N3 possesses a high inhibitory action. In addition, the in vitro studies demonstrated that the whole tested 1,2,4-triazole are potent inhibitors with a Ki magnitude of 10-6 and exhibited a competitive type inhibition. On the other hand, the thioglycosides - based imidazole ring showed an antioxidant activity and exerted a slight in vivo stimulation of α-glucosidase and β- glucuronidase. Molecular docking proved that the compounds exhibited binding affinity with the active sites of α -glucosidase and β-glucuronidase (docking score ranged from -2.320 to -4.370 kcal/mol). Furthermore, QSAR study revealed that the HBD and RB were found to have an overall significant correlation with the toxicity. Conclusion: These data suggest that the inhibition of α-glucosidase is accompanied by an oxidative stress action.

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