Bioinformatics approaches to investigate the phytochemicals of Centella asiatica against the main protease of SARS-CoV-2

Abstract The recent pandemic caused by the novel coronavirus SARS-CoV-2 has impacted global health by increasing mortality and unexpected infection rate. Extensive clinical research is undergoing to repurposing the old drug against this virus. So, this is an emerging need to develop therapy against the virus. Plant-derived natural products have proven to be potent therapeutics for several infections and diseases. Centella asiatica, is a native plant of the Indian subcontinent, has been vastly using as folk medicine against diseases including infectious diseases. So, using bioinformatics approach we identified and checked the phytochemicals of the plant as inhibitors against the main protease (Mpro), the key regulatory enzyme of the SARS-CoV-2 lifecycle. Computer-aided drug designing methods were performed to reveal the best nine drug-like phytochemicals those theoretically have the higher binding affinity of inhibiting Mpro. This outcome may direct to the development of potent therapeutics against the SARS-CoV-2 and demands experimental validation.

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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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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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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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Exposure to Morning Sunlight/Ultraviolet B (UV-B) Radiations (290–320nm) Decreases the Risk of COVID-19: India (Preprint)

10.2196/preprints.19990 ◽

2020 ◽

Author(s):

Sharuk Khan ◽

Falak Siddiqui ◽

Shirish Jain

Keyword(s):

Vitamin D ◽

Indian Subcontinent ◽

Poverty Line ◽

Ultraviolet B ◽

Optimum Level ◽

The Novel ◽

Normal Ranges ◽

Vitamin D Levels ◽

Novel Coronavirus ◽

Tract Infections

UNSTRUCTURED The novel coronavirus 2019-nCoV/SARS-CoV-2 that has caused the outbreak of the coronavirus disease, COVID-19, has created an alarming situation around the world, including India. Vitamin D is a hormone precursor that plays an important role in adaptive immunity, cellular differentiation, maturation, and proliferation of immune cells. The optimum level of vitamin D could be a potential lead to fight against SARS-CoV-2 infection. In the Indian subcontinent, Vitamin D deficiency prevails in wide-ranging proportions, with a prevalence of 70%–100%. Vitamin D produced in the skin by sunlight/ultraviolet B (UV-B) radiation (290–320nm) may last in the blood twice compared with supplementary vitamin D, wherein consuming vitamin D through supplementary source may lead to toxicity. Balancing vitamin D levels between normal ranges will be effective and cheap to control and/or to prevent respiratory tract infections (RTIs). Although, if we talk about India, it is challenging to provide vitamin D through the supplementary source to every individual, and also it will not be affordable for people of below poverty line (BPL). Therefore, the optimum level of vitamin D could be a potential lead to fight against SARS-CoV-2 infection, which could be achieved by proper exposure to sunlight (preferably in the morning) for 10-20 min daily.

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Didemnins Inhibit COVID-19 Main Protease (Mpro)

Biointerface Research in Applied Chemistry ◽

10.33263/briac111.82048209 ◽

2020 ◽

Vol 11 (1) ◽

pp. 8204-8209

Keyword(s):

Prediction Method ◽

Target Prediction ◽

Docking Studies ◽

Therapeutic Agents ◽

The Novel ◽

Main Protease ◽

Docking Method ◽

Marine Compounds ◽

Novel Coronavirus ◽

Therapeutic Alternatives

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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Fighting COVID-19

Brazilian Journal of Biology ◽

10.1590/1519-6984.238155 ◽

2020 ◽

Vol 80 (3) ◽

pp. 698-701 ◽

Cited By ~ 2

Author(s):

D. M. O. Campos ◽

C. B. S. Oliveira ◽

J. M. A. Andrade ◽

J. I. N. Oliveira

Keyword(s):

Drug Targets ◽

Vaccine Development ◽

High Rate ◽

The Novel ◽

Rate Of Spread ◽

Specific Effects ◽

Main Protease ◽

Clinical Strategies ◽

Novel Coronavirus ◽

Transmembrane Serine Protease

Abstract The current COVID-19 pandemic caused by the novel coronavirus (SARS-CoV2) poses a threat to global health owing to its high rate of spread and severe forms of respiratory infection. The lack of vaccines and antivirals prevents clinical strategies against the disease, creating an emerging need for the development of safe and effective treatments. Strategies for vaccine development include complete vaccines against viruses, subunits, and nucleic acids, but are still in their early stages. Studies carried out to date on possible SARS-CoV2 drug targets highlight glycoprotein S, Mpro (main protease or protease type 3C), and a member of the transmembrane serine protease II families (TMPRSS2). However, due to the pandemic state, priority is given to marketed drugs. These include chloroquine (CQ), hydroxychloroquine (HCQ), nitazoxanide, remdesivir, Lopinavir/ritonavir (LPV / r), in addition to treatment with convalescent plasma. But, therapeutic specific effects against SARS-CoV2 have not yet been verified. Most of the information obtained about treatment is based on preliminary and limited studies. We conclude that, at this time of emergency, the search for new therapies is more urgent due to the need to save lives. Thus, we point out as interesting targets for future more specific research: glycoprotein S, Mpro, and TMPRSS2.

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Biochemical and biophysical characterization of the main protease, 3-chymotrypsin-like protease (3CLpro) from the novel coronavirus SARS-CoV 2

Scientific Reports ◽

10.1038/s41598-020-79357-0 ◽

2020 ◽

Vol 10 (1) ◽

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

AbstractSevere 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 may 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 discovery of drugs and design of antiviral therapeutics against COVID-19.

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