Didemnins Inhibit COVID-19 Main Protease (Mpro)

The novel coronavirus disease because of infection with the SARS-CoV-2 virus, COVID-19, was first appeared in Wuhan, China, in December 2019. It has spread rapidly all around the World and has been accepted as a pandemic. Specific therapies for COVID-19 treatment is not available for now. Thus, there is a huge effort to develop and discover new therapeutic agents and vaccines by scientists. The design and development of new therapeutic agents for treatment through medicinal chemistry is slow and needed a hard labor process. Thus, it is urgent to achieve the discovery of more effective agents. Marine natural products have antiviral activity and quite significant pharmacological capacity. The antiviral properties of these products are shown as new promising therapeutic alternatives against the viruses. The present work aimed to assess the inhibition potential of Didemnin A, B, and C isolated from tunicates to COVID-19 Mpro protein through a molecular docking method. The molecular characterization of compounds with binding affinity was performed by using the Swiss Target Prediction Method. As a result, the binding energy of Didemnins A, B, and C was calculated as -11.82 kcal/ mol, -10.27 kcal/ mol, and -9.26 kcal/ mol, respectively. Also, the docking studies showed that Didemnin B involved in hydrogen bonding with Glu166 in the active site of the Mpro protein. Therefore, the natural marine compounds have the potential for developing drugs against to SARS-CoV-2 virus, which may aid in overcoming the clinical challenge of the COVID-19 pandemic.

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Discovery of alliin as a putative inhibitor of the main protease of SARS-CoV-2 by molecular docking

BioTechniques ◽

10.2144/btn-2020-0038 ◽

2020 ◽

Vol 69 (2) ◽

pp. 108-112 ◽

Cited By ~ 1

Author(s):

Bijun Cheng ◽

Tianjiao Li

Keyword(s):

Molecular Docking ◽

Pharmaceutical Compounds ◽

The Novel ◽

Important Target ◽

Main Protease ◽

Docking Method ◽

Life Threatening ◽

Novel Coronavirus ◽

Better Than ◽

Molecular Docking Method

The outbreak of viral pneumonia caused by the novel coronavirus SARS-CoV-2 that began in December 2019 caused high mortality. It has been suggested that the main protease (Mpro) of SARS-CoV-2 may be an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. Remdesivir, ritonavir and chloroquine have all been reported to play a role in suppressing SARS-CoV-2. Here, we applied a molecular docking method to study the binding stability of these drugs with SARS-CoV-2 Mpro. It appeared that the ligand–protein binding stability of the alliin and SARS-CoV-2 Mpro complex was better than others. The results suggested that alliin may serve as a good candidate as an inhibitor of SARS-CoV-2 Mpro. Therefore, the present research may provide some meaningful guidance for the prevention and treatment of SARS-CoV-2.

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Screening of Kabasura Kudineer Chooranam against COVID-19 through Targeting of Main Protease and RNA-Dependent RNA Polymerase of SARS-CoV-2 by Molecular Docking Studies

Asian Journal of Organic & Medicinal Chemistry ◽

10.14233/ajomc.2020.ajomc-p299 ◽

2020 ◽

Vol 5 (4) ◽

pp. 319-331

Author(s):

K. Gopalasatheeskumar ◽

Karthikeyen Lakshmanan ◽

Anguraj Moulishankar ◽

Jerad Suresh ◽

D. Kumuthaveni Babu ◽

...

Keyword(s):

Molecular Docking ◽

Rna Polymerase ◽

Docking Studies ◽

The Novel ◽

Rna Dependent Rna Polymerase ◽

Molecular Docking Studies ◽

Main Protease ◽

Short Span ◽

Novel Coronavirus

COVID-19 is the infectious pandemic disease caused by the novel coronavirus. The COVID-19 is spread globally in a short span of time. The Ministry of AYUSH, India which promotes Siddha and other Indian system of medicine recommends the use of formulation like Nilavembu Kudineer and Kaba Sura Kudineer Chooranam (KSKC). The present work seeks to provide the evidence for the action of 74 different constituents of the KSKC formulation acting on two critical targets. That is main protease and SARS-CoV-2 RNAdependent RNA polymerase target through molecular docking studies. The molecular docking was done by using AutoDock Tools 1.5.6 of the 74 compounds, about 50 compounds yielded docking results against COVID-19 main protease while 42 compounds yielded against SARSCoV- 2 RNA-dependent RNA polymerase. This research has concluded that the KSKC has the lead molecules that inhibits COVID-19’s target of main protease of COVID-19 and SARS-CoV-2 RNA-dependent RNA polymerase.

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Comparative docking of SARS-CoV-2 receptors antagonists from repurposing drugs

10.26434/chemrxiv.12044538.v4 ◽

2020 ◽

Author(s):

Micael Davi Lima de Oliveira ◽

Kelson Mota Teixeira de Oliveira

Keyword(s):

World Health Organisation ◽

World Health ◽

Lung Cells ◽

The Novel ◽

High Modulation ◽

Main Protease ◽

The World ◽

Novel Coronavirus ◽

Viral Receptors ◽

Theoretical Results

According to the World Health Organisation, until 16 June, 2020, the number of confirmed and notified cases of COVID-19 has already exceeded 7.9 million with approximately 434 thousand deaths worldwide. This research aimed to find repurposing antagonists, that may inhibit the activity of the main protease (Mpro) of the SARS-CoV-2 virus, as well as partially modulate the ACE2 receptors largely found in lung cells, and reduce viral replication by inhibiting Nsp12 RNA polymerase. Docking molecular simulations were performed among a total of 60 structures, most of all, published in the literature against the novel coronavirus. The theoretical results indicated that, in comparative terms, paritaprevir, ivermectin, ledipasvir, and simeprevir, are among the most theoretical promising drugs in remission of symptoms from the disease. Furthermore, also corroborate indinavir to the high modulation in viral receptors. The second group of promising drugs includes remdesivir and azithromycin. The repurposing drugs HCQ and chloroquine were not effective in comparative terms to other drugs, as monotherapies, against SARS-CoV-2 infection.

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Quinoline and Quinazoline Alkaloids against COVID-19: An In Silico Multitarget Approach

Journal of Chemistry ◽

10.1155/2021/3613268 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Esraa M. O. A. Ismail ◽

Shaza W. Shantier ◽

Mona S. Mohammed ◽

Hassan H. Musa ◽

Wadah Osman ◽

...

Keyword(s):

Antimalarial Activity ◽

The Novel ◽

Socioeconomic Impacts ◽

Health Crisis ◽

Natural Sources ◽

Angiotensin Converting Enzyme 2 ◽

Main Protease ◽

Recent Outbreak ◽

Novel Coronavirus ◽

Potential Inhibitors

The recent outbreak of the highly contagious coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 has created a global health crisis with socioeconomic impacts. Although, recently, vaccines have been approved for the prevention of COVID-19, there is still an urgent need for the discovery of more efficacious and safer drugs especially from natural sources. In this study, a number of quinoline and quinazoline alkaloids with antiviral and/or antimalarial activity were virtually screened against three potential targets for the development of drugs against COVID-19. Among seventy-one tested compounds, twenty-three were selected for molecular docking based on their pharmacokinetic and toxicity profiles. The results identified a number of potential inhibitors. Three of them, namely, norquinadoline A, deoxytryptoquivaline, and deoxynortryptoquivaline, showed strong binding to the three targets, SARS-CoV-2 main protease, spike glycoprotein, and human angiotensin-converting enzyme 2. These alkaloids therefore have promise for being further investigated as possible multitarget drugs against COVID-19.

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Biochemical and Biophysical characterization of the main protease, 3-chymotrypsin-like protease (3CLpro), from the novel coronavirus disease 19 (COVID-19)

10.21203/rs.3.rs-40945/v1 ◽

2020 ◽

Author(s):

Juliana C. Ferreira ◽

Wael M. Rabeh

Keyword(s):

Antiviral Drug ◽

Analytical Techniques ◽

The Novel ◽

Buffer Solution ◽

Biophysical Characterization ◽

Main Protease ◽

Wide Ph Range ◽

The Stability ◽

Ph Range ◽

Novel Coronavirus

Abstract Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is responsible for the novel coronavirus disease 2019 (COVID-19). An appealing antiviral drug target is the coronavirus 3C-like protease (3CLpro) that is responsible for the processing of the viral polyproteins and liberation of functional proteins essential for the maturation and infectivity of the virus. In this study, multiple thermal analytical techniques have been implemented to acquire the thermodynamic parameters of 3CLpro at different buffer conditions. 3CLpro exhibited relatively high thermodynamic stabilities over a wide pH range; however, the protease was found to be less stable in the presence of salts. Divalent metal cations reduced the thermodynamic stability of 3CLpro more than monovalent cations; however, altering the ionic strength of the buffer solution did not alter the stability of 3CLpro. Furthermore, the most stable thermal kinetic stability of 3CLpro was recorded at pH 7.5, with the highest enthalpy of activation calculated from the slope of Eyring plot. The biochemical and biophysical properties of 3CLpro explored here will improve the solubility and stability of 3CLpro for optimum conditions for the setup of an enzymatic assay for the screening of inhibitors to be used as lead candidates in the drug discovery and antiviral design for therapeutics against COVID-19.

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X-ray Structure of Main Protease of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors

10.1101/2020.02.17.952879 ◽

2020 ◽

Cited By ~ 4

Author(s):

Linlin Zhang ◽

Daizong Lin ◽

Xinyuanyuan Sun ◽

Katharina Rox ◽

Rolf Hilgenfeld

Keyword(s):

Crystal Structure ◽

Crystal Structures ◽

Atypical Pneumonia ◽

The Novel ◽

Replication Complex ◽

X Ray ◽

Main Protease ◽

Pharmacokinetic Properties ◽

Novel Coronavirus ◽

Further Development

AbstractA novel coronavirus has been identified as the causative agent of a massive outbreak of atypical pneumonia originating at Wuhan, Hubei province, China. Involved in the formation of the coronavirus replication complex, the viral main protease (Mpro, also called 3CLpro) represents an attractive target for therapy. We determined the crystal structure of the unliganded Mpro at 1.75 Å resolution and used this structure to guide optimization of a series of alpha-ketoamide inhibitors. The main goal of the optimization efforts was improvement of the pharmacokinetic properties of the compounds. We further describe 1.95- and 2.20-Å crystal structures of the complex between the enzyme and the most potent alpha-ketoamide optimized this way. These structures will form the basis for further development of these compounds to antiviral drugs.

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Evaluation of Yashtimadhu (Glycyrrhiza glabra) active Phytochemicals Against Novel Coronavirus (SARS-CoV-2)

10.21203/rs.3.rs-26480/v1 ◽

2020 ◽

Author(s):

Dharmendra Kumar Maurya

Keyword(s):

Viral Entry ◽

Virus Disease ◽

Scientific Basis ◽

Docking Studies ◽

Angiotensin Converting Enzyme 2 ◽

Main Protease ◽

Docking Approach ◽

Novel Coronavirus ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract Corona Virus Disease 2019 (COVID-19) caused by a novel coronavirus emerged from Wuhan, China in December 2019. It has spread to more than 205 countries and become pandemic now. Currently, there are no FDA approved drugs or vaccines available and hence several studies are going on in search of suitable drug that can target viral proteins or host receptor for the prevention and management of COVID-19. The search for plant-based anti-viral agents against the SARS-CoV-2 is promising because several of plants have been shown to possess anti-viral activities against different viruses. Here, we used molecular docking approach to explore the use of Indian Ayurvedic herbs, Yashtimadhu in prevention and management of COVID-19. In the present study we have evaluated the effectiveness of phytochemicals found in Yashtimadhu against Main Protease (Mpro), Spike (S) protein and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 as well as human angiotensin converting enzyme 2 (ACE2) receptor and furin protease. Apart from this, we have also performed in-silico drug-likeness and predicted pharmacokinetics of the selected phytochemicals found in the Yashtimadhu. Our study shows that several phytochemicals found in this plant have potential to bind with important proteins of SARS-CoV-2 which are essential for viral infection and replication. Overall our study provides scientific basis in terms of binding of active ingredients present in Yashtimadhu with SARS-CoV-2 target proteins. Our docking studies reveal that Yashtimadhu may inhibit the viral severity by interfering with viral entry as well as its multiplication in the infected persons. Thus Yashtimadhu may be helpful in the prevention and management of the COVID-19.

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Antiviral potential of phytoligands against chymotrypsin-like protease of COVID‐19 virus using molecular docking studies: An optimistic approach

10.21203/rs.3.rs-23956/v1 ◽

2020 ◽

Author(s):

Ratish Chandra Mishra ◽

Rosy Kumari ◽

Shivani Yadav ◽

Jaya Parkash Yadav

Keyword(s):

Molecular Docking ◽

Binding Energy ◽

Drug Repositioning ◽

Docking Studies ◽

The Novel ◽

Lead Compounds ◽

Recent Outbreak ◽

Novel Coronavirus ◽

The City ◽

Ucsf Chimera

Abstract A recent outbreak of the novel coronavirus, COVID‐19, in the city of Wuhan, Hubei province, China and its ensuing worldwide spread have resulted in lakhs of infections and thousands of deaths. As of now, there are no registered therapies for treating the contagious COVID‐19 infections, henceforth drug repositioning may provide a fast way out. In the present study, a total of thirty-five compounds including commonly used anti-viral drugs were screened against chymotrypsin-like protease (3CLpro) using SwissDock. Interaction between amino acid of targeted protein and ligands was visualized by UCSF Chimera. Docking studies revealed that the phytochemicals such as cordifolin, anisofolin A, apigenin 7-glucoside, luteolin, laballenic acid, quercetin, luteolin-4-glucoside exhibited significant binding energy with the enzyme viz. - 8.77, -8.72, -8.36, -8.35, -8.13, -8.04 and -7.87 Kcal/Mol respectively. Therefore, new lead compounds can be used for drug development against SARS‐CoV‐2 infections.

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In Silico Identification and Docking-Based Drug Repurposing Against the Main Protease of SARS-CoV-2, Causative Agent of COVID-19

10.26434/chemrxiv.12049590.v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Yogesh Kumar ◽

Harvijay Singh

Keyword(s):

Virtual Screening ◽

Active Site ◽

Viral Infections ◽

Drug Repurposing ◽

Docking Study ◽

Docking Studies ◽

Main Protease ◽

Novel Coronavirus ◽

Approved Drugs

<div>The rapidly enlarging COVID-19 pandemic caused by novel SARS-coronavirus 2 is a global</div><div>public health emergency of unprecedented level. Therefore the need of a drug or vaccine that</div><div>counter SARS-CoV-2 is an utmost requirement at this time. Upon infection the ssRNA genome</div><div>of SARS-CoV-2 is translated into large polyprotein which further processed into different</div><div>nonstructural proteins to form viral replication complex by virtue of virus specific proteases:</div><div>main protease (3-CL protease) and papain protease. This indispensable function of main protease</div><div>in virus replication makes this enzyme a promising target for the development of inhibitors and</div><div>potential treatment therapy for novel coronavirus infection. The recently concluded α-ketoamide</div><div>ligand bound X-ray crystal structure of SARS-CoV-2 Mpro (PDB ID: 6Y2F) from Zhang et al.</div><div>has revealed the potential inhibitor binding mechanism and the determinants responsible for</div><div>involved molecular interactions. Here, we have carried out a virtual screening and molecular</div><div>docking study of FDA approved drugs primarily targeted for other viral infections, to investigate</div><div>their binding affinity in Mpro active site. Virtual screening has identified a number of antiviral</div><div>drugs, top ten of which on the basis of their bending energy score are further examined through </div><div>molecular docking with Mpro. Docking studies revealed that drug Lopinavir-Ritonavir, Tipranavir</div><div>and Raltegravir among others binds in the active site of the protease with similar or higher</div><div>affinity than the crystal bound inhibitor α-ketoamide. However, the in-vitro efficacies of the drug</div><div>molecules tested in this study, further needs to be corroborated by carrying out biochemical and</div><div>structural investigation. Moreover, this study advances the potential use of existing drugs to be</div><div>investigated and used to contain the rapidly expanding SARS-CoV-2 infection.</div>

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Nanotechnology against the novel coronavirus (severe acute respiratory syndrome coronavirus 2): diagnosis, treatment, therapy and future perspectives

Nanomedicine ◽

10.2217/nnm-2020-0441 ◽

2021 ◽

Vol 16 (6) ◽

pp. 497-516

Author(s):

Hamid Rashidzadeh ◽

Hossein Danafar ◽

Hossein Rahimi ◽

Faezeh Mozafari ◽

Marziyeh Salehiabar ◽

...

Keyword(s):

Infectious Disease ◽

Therapeutic Agents ◽

Rapid Diagnosis ◽

Socioeconomic Impact ◽

The Novel ◽

Future Perspectives ◽

Mortality And Morbidity ◽

Self Assembling ◽

Novel Coronavirus ◽

Significant Mortality

COVID-19, as an emerging infectious disease, has caused significant mortality and morbidity along with socioeconomic impact. No effective treatment or vaccine has been approved yet for this pandemic disease. Cutting-edge tools, especially nanotechnology, should be strongly considered to tackle this virus. This review aims to propose several strategies to design and fabricate effective diagnostic and therapeutic agents against COVID-19 by the aid of nanotechnology. Polymeric, inorganic self-assembling materials and peptide-based nanoparticles are promising tools for battling COVID-19 as well as its rapid diagnosis. This review summarizes all of the exciting advances nanomaterials are making toward COVID-19 prevention, diagnosis and therapy.

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