Design of ZnO-Drug Nanocarriers against the Main Protease of SARS-CoV-2 (COVID-19): An In Silico Assay

The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of Zingiber offinale and Anacardium occidentale using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of Zingiber offinale and the leaves of Anacardium occidentale. These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), Pan-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907).

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In Silico Molecular Docking and Molecular Dynamic Simulation of Potential Inhibitors of 3C-like Main Proteinase (3CLpro) from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Using Selected African Medicinal Plants

10.26434/chemrxiv.12480434 ◽

2020 ◽

Author(s):

Sahar Qazi ◽

Mustafa Alhaji Isa ◽

Adam Mustapha ◽

Khalid Raza ◽

Ibrahim Alkali Allamin ◽

...

Keyword(s):

Molecular Docking ◽

Severe Acute Respiratory Syndrome ◽

In Silico ◽

Md Simulation ◽

Binding Energies ◽

Anacardium Occidentale ◽

Upper Respiratory Tract ◽

Ligand Complex ◽

In Silico Docking ◽

Main Protease

The Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) is an infectious virus that causes mild to severe life-threatening upper respiratory tract infection. The virus emerged in Wuhan, China in 2019, and later spread across the globe. Its genome has been completely sequenced and based on the genomic information, the virus possessed 3C-Like Main Protease (3CLpro), an essential multifunctional enzyme that plays a vital role in the replication and transcription of the virus by cleaving polyprotein at eleven various sites to produce different non-structural proteins. This makes the protein an important target for drug design and discovery. Herein, we analyzed the interaction between the 3CLpro and potential inhibitory compounds identified from the extracts of Zingiber offinale and Anacardium occidentale using in silico docking and Molecular Dynamics (MD) Simulation. The crystal structure of SARS-CoV-2 main protease in complex with 02J (5-Methylisoxazole-3-carboxylic acid) and PEJ (composite ligand) (PDB Code: 6LU7,2.16Å) retrieved from Protein Data Bank (PDB) and subject to structure optimization and energy minimization. A total of twenty-nine compounds were obtained from the extracts of Zingiber offinale and the leaves of Anacardium occidentale. These compounds were screened for physicochemical (Lipinski rule of five, Veber rule, and Egan filter), Pan-Assay Interference Structure (PAINS), and pharmacokinetic properties to determine the Pharmaceutical Active Ingredients (PAIs). Of the 29 compounds, only nineteen (19) possessed drug-likeness properties with efficient oral bioavailability and less toxicity. These compounds subjected to molecular docking analysis to determine their binding energies with the 3CLpro. The result of the analysis indicated that the free binding energies of the compounds ranged between ˗5.08 and -10.24kcal/mol, better than the binding energies of 02j (-4.10kcal/mol) and PJE (-5.07kcal.mol). Six compounds (CID_99615 = -10.24kcal/mol, CID_3981360 = 9.75kcal/mol, CID_9910474 = -9.14kcal/mol, CID_11697907 = -9.10kcal/mol, CID_10503282 = -9.09kcal/mol and CID_620012 = -8.53kcal/mol) with good binding energies further selected and subjected to MD Simulation to determine the stability of the protein-ligand complex. The results of the analysis indicated that all the ligands form stable complexes with the protein, although, CID_9910474 and CID_10503282 had a better stability when compared to other selected phytochemicals (CID_99615, CID_3981360, CID_620012, and CID_11697907).

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Possible Targets and Therapies of SARS-CoV-2 Infection

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666200807131855 ◽

2020 ◽

Vol 20 (18) ◽

pp. 1900-1907

Author(s):

Kasturi Sarkar ◽

Parames C. Sil ◽

Seyed Fazel Nabavi ◽

Ioana Berindan-Neagoe ◽

Cosmin Andrei Cismaru ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Viral Replication ◽

Viral Infection ◽

Human Activity ◽

Viral Proteins ◽

Therapeutic Agents ◽

Effective Control ◽

Human Society ◽

Global Spread ◽

Repurposed Drugs

The global spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes COVID-19 has become a source of grave medical and socioeconomic concern to human society. Since its first appearance in the Wuhan region of China in December 2019, the most effective measures of managing the spread of SARS-CoV-2 infection have been social distancing and lockdown of human activity; the level of which has not been seen in our generations. Effective control of the viral infection and COVID-19 will ultimately depend on the development of either a vaccine or therapeutic agents. This article highlights the progresses made so far in these strategies by assessing key targets associated with the viral replication cycle. The key viral proteins and enzymes that could be targeted by new and repurposed drugs are discussed.

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SARS-CoV-2 Seroprevalence among Healthcare Workers in General Hospitals and Clinics in Japan

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18073786 ◽

2021 ◽

Vol 18 (7) ◽

pp. 3786

Author(s):

Tatsuya Yoshihara ◽

Kazuya Ito ◽

Masayoshi Zaitsu ◽

Eunhee Chung ◽

Izumi Aoyagi ◽

...

Keyword(s):

Public Health ◽

Social Support ◽

General Population ◽

Severe Acute Respiratory Syndrome ◽

Immunoglobulin G ◽

Health Problem ◽

Healthcare Workers ◽

Public Health Problem ◽

General Hospitals ◽

Second Wave

Coronavirus disease 2019 (COVID-19) has become a serious public health problem worldwide. In general, healthcare workers are considered to be at higher risk of COVID-19 infection. However, the prevalence of COVID-19 among healthcare workers in Japan is not well characterized. In this study, we aimed to examine the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies among 2160 healthcare workers in hospitals and clinics that are not designated to treat COVID-19 patients in Japan. The prevalence of SARS-CoV-2 immunoglobulin G was 1.2% in August and October 2020 (during and after the second wave of the pandemic in Japan), which is relatively higher than that in the general population in Japan (0.03–0.91%). Because of the higher risk of COVID-19 infection, healthcare workers should be the top priority for further social support and vaccination against SARS-CoV-2.

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The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro

Viruses ◽

10.3390/v13050873 ◽

2021 ◽

Vol 13 (5) ◽

pp. 873

Author(s):

Raphael J. Eberle ◽

Danilo S. Olivier ◽

Marcos S. Amaral ◽

Ian Gering ◽

Dieter Willbold ◽

...

Keyword(s):

Binding Mode ◽

Drug Candidates ◽

Main Protease ◽

Ic50 Values ◽

Repurposed Drugs ◽

Antiparasitic Drugs ◽

Inhibitory Potential ◽

Dynamics Simulations ◽

Micromolar Range

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

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Preventive aspect of ayurveda and yoga towards newly emerging disease COVID-19

Journal of Complementary and Integrative Medicine ◽

10.1515/jcim-2020-0175 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Ranjeet S. Sawant ◽

Bharat D. Zinjurke ◽

Sandeep V. Binorkar

Keyword(s):

Public Health ◽

Severe Acute Respiratory Syndrome ◽

Medical Care ◽

Supportive Therapy ◽

Prophylactic Therapy ◽

Current Line ◽

Therapeutic Aspect ◽

The Past

Abstract The ongoing coronavirus pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) and unique in various facets. The earlier experience from the past severe acute respiratory syndrome (SARS) epidemics seem to be insufficient and there is need for better strategies in public health and medical care. Ayurved & Yog are well known for their preventive and therapeutic aspect, but not getting utilized properly for prevention of Covid 19 crisis which may also be helpful as supportive therapy along with current line of management. This paper is aimed at unrevealing the role of Ayurved and Yoga guidelines established by Department of AYUSH for prevention from SARS-CoV-2 by providing help to improving the quality of supportive/prophylactic therapy in relation with their immunity.

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Vitamin D, SARS-CoV-2 and Causal Associations in Transversal Studies: The Time-Series Analysis to Reveal Potential Confounders. Comment on Gaudio et al. Vitamin D Levels Are Reduced at the Time of Hospital Admission in Sicilian SARS-CoV-2-Positive Patients. Int. J. Environ. Res. Public Health 2021, 18, 3491

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18136793 ◽

2021 ◽

Vol 18 (13) ◽

pp. 6793

Author(s):

Cristiano Ialongo ◽

Antonella Farina ◽

Raffaella Labriola ◽

Antonio Angeloni ◽

Emanuela Anastasi

Keyword(s):

Public Health ◽

Vitamin D ◽

Time Series ◽

Severe Acute Respiratory Syndrome ◽

Time Series Analysis ◽

Hospital Admission ◽

The State ◽

Series Analysis ◽

Vitamin D Levels ◽

Time Of Admission

We read with great interest the paper by Gaudio and colleagues on vitamin D and on the state of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the time of admission [...]

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Broad-Spectrum Antiviral Strategies and Nucleoside Analogues

Viruses ◽

10.3390/v13040667 ◽

2021 ◽

Vol 13 (4) ◽

pp. 667

Author(s):

Robert J. Geraghty ◽

Matthew T. Aliota ◽

Laurent F. Bonnac

Keyword(s):

Public Health ◽

Severe Acute Respiratory Syndrome ◽

Broad Spectrum ◽

Vaccine Development ◽

Fast Response ◽

Mechanisms Of Action ◽

Public Health Emergency ◽

Nucleoside Analogues ◽

The Family ◽

Antiviral Nucleoside

The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and SARS-CoV-2) viruses, or new strains of influenza represents significant human health threats due to the absence of available treatments. Vaccines represent a key answer to control these viruses. However, in the case of a public health emergency, vaccine development, safety, and partial efficacy concerns may hinder their prompt deployment. Thus, developing broad-spectrum antiviral molecules for a fast response is essential to face an outbreak crisis as well as for bioweapon countermeasures. So far, broad-spectrum antivirals include two main categories: the family of drugs targeting the host-cell machinery essential for virus infection and replication, and the family of drugs directly targeting viruses. Among the molecules directly targeting viruses, nucleoside analogues form an essential class of broad-spectrum antiviral drugs. In this review, we will discuss the interest for broad-spectrum antiviral strategies and their limitations, with an emphasis on virus-targeted, broad-spectrum, antiviral nucleoside analogues and their mechanisms of action.

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