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To determine the structure of substrate Mpro present in the COVID-19 virus and identify its inhibiting agents.

Task brief:

The word limit should be 1000 words (±10%)

Each Journal report should consist of the following:

Title page: This should be your own title.

Following page: student name, ID, module and programme information.

Journal critique:

Abstract (no more than 150 words): Follow the instructions that I have uploaded. This should be your own abstract based on your understanding of the article.

You should critique on the abstract of the article if the authors have addressed all the key points

If the abstract is not clear, then suggest what information is missing.

Solution:

Abstract

The abstract presented by the author provided an explicit account of the COVID-19 virus which is a novel coronavirus (CoV) strain. The author has presented a clear view about the etiological cause of the viral illness that originated in China in 2019-2020 and has spread across the globe. But the abstract lacks a descriptive account of COVID-19 health effects on a specific in terms of mutation and its spike protein. The outstanding description of the study results help in identifying the chemical structure of the COVID-19 virus Mpro presented a succinate description of its link with the chemical compound. It is strongly argued that the researchers provided a clear structural analysis integration of structure-based virtual as well as presented increased screening approaches for testing over 10,000 compounds for their ability to inhibit Mpro. But the abstract lacked the information regarding the research methodology used for the purpose of the study and the benefit of inhibiting agents in fighting against the virus. 

Aim

The authors tried to achieve analytical review about facilitating the rapid discovery of antiviral compounds and work to achieve a structure-assisted drug design combined with virtual drug screening as well as target COVID-19 virus along with clear focus presented on inhibiting agents which will assist in the formulation of effective anti-viral therapy for the global illness. 

Introduction

The background of the research presented a clear view about the CoV as the causative pathogens that results in a wide range of highly prevailing and severe diseases such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) (MERS) (Kanhed et al., 2021). But it lacked the gene description in terms of relevance and significance to humans. A contrasting analytical view was strongly presented in the study about the Mpro’s functional importance in the life cycle of the virus as well as the impact of the absence of the lack of closely linked homologs in humans. This clearly addressed as to how Mpro protein has emerged as a prospective target for antiviral drug development (Rajpoot, Alagumuthu and Baig, 2021).

The background presents a relevant literature review about the structure of the viral particles but did not reconstruct around the current medications to target the COVID-19 virus Mpro. The study background presented the evidence-based strategy of how researchers have devised a technique that integrates structure-assisted drug design (SAD), virtual drug screening (VDS), and high-throughput screening. The article background established a methodology that involved a hybrid of structure-based drug design, virtual drug screening, and high-throughput screening to uncover new therapeutic leads that target the COVID-19 viral major protease as fast as feasible for clinical usage. The background presents clear evidence to the hypothesis that, shortly, the identification of a single antiviral medication that targets Mpro, either alone or in alliance with different possible treatments, might act as an efficient initial layer of protection against all CoV-associated illnesses. But it did not address what is the significance of the study and why it is being undertaken in terms of addressing problems in the available literature. But it presents a non-strategic plan in terms of methodologies used in the research, which might accelerate the development of therapeutic probabilities with clinical efficiencies in reaction to novel emerging infection-causing disorders for which no treatment is currently available (Sacco et al., 2020).

Methods

The methodology of the research study involved the following steps:

  • Mpro of the COVID-19 virus was cloned, expressed as a protein, and purified
  • Data collection and structure determination are all part of the crystallization process.
  • Activity and inhibition assays for enzymatic enzymes
  • Enzymatic activity and inhibition assays are carried out.
  • Molecular docking is indeed a mechanism for linking molecules.
  • Assays for detecting the antiviral and cytotoxic activities of chemicals discovered through high-throughput screening
  • Antiviral and cytotoxicity experiments, as well as plaque-reduction screening, have been done on cinanserin.
  • Intact protein analysis
  • Analysis of tandem mass spectrometry

As per a critical view, various other methodologies that can be used for this research article are prioritizing SARS –COV-2 chief protease that forms a leading and efficient target of the anti-viral drug. Also, the methodology can be easily replicated by other researchers but it lacks a clear workflow in terms of identifying the preferences regarding substrates of SARS-CoV and SARS-CoV2 proteases. The results as found in other studies offer a systematic model that will help in the discovery of efficient antiviral agents (Zhang and Guo, 2020). The study methodologies should be presented in the article in a more descriptive view and an outstanding aspect is presented via using multiple images which will assist future researchers to draw implications. Both the researches ultimately identify the effective antiviral drug against the virus through the primary proteases (Zhang et al., 2020).

Results:

The study clearly did not utilize any control but the researchers utilized many variables which made this study authentic. But it is strongly argued that the report did not present any statistical evaluation of effects. The results focus on presenting a logical connection in terms of determining the crystalline structure of Mpro of SARS-CoV-2 in collaboration with the inhibitor after establishing an inhibiting agent named (N3) using an automated drug design. The study must filter the results in terms of the huge diversity of 10,000 compounds for Mpro inhibition which utilized only a blend of structure-based modelling and elevated screening. Also, the major weakness lies in terms of the lack of any comparative results. But it presents a major strength of datasets in terms of extended Data and a descriptive design of data collection and refinement statistics. The researchers firmly support that the screening technique has the potential to quickly identify therapeutic agents having clinical efficacy in response to developing communicable disorders for which no particular treatment is currently available. The figures and tables present descriptive legends and explanations about the graphs in terms of data labels which increase the relevance and authenticity of the results. The major findings of the study adhere to the pilot study which emphasizes offering a treatment solution to a virus that has disrupted millions of people. The protease namely Mpro has specific binding sites and these enable the inhibitors to bind at these locations and will work as a potent antiviral agent against the infection. 

Discussion

The results did not adhere to the hypothesis presented by the author and the study must discuss the software used for molecular docking and the potential disadvantages of the analysis methods. But the authors are not open-minded as they have not discussed any other possible methodologies that might bring similar or more effective results. Also, there is a need of discussing the other possibilities in terms of the crystalline structure analysis about the discovery of a potent antiviral drug against a deadly virus. Thus it is much needed that a comprehensive analysis of the structure of the virus renders the information about the chief protease named Mpro which is a crucial CoV enzyme that is responsible for viral multiplication and transcription and makes it an efficient drug target against the microorganism. 

Conclusion and future directions                   

The research study lacked adherence to a hypothesis and could not clearly identify a potent antiviral agent that can be used individually or in a combination of other drugs with the help of identification of the structure of the substrate. Thus there is a need to develop more potent antiviral agents which are effective against deadly viruses with the use of improved molecular mocking techniques. Also, rather than focussing on the crystal structure and binding to the substrate-binding pocket of the COVID-19 virus, it must focus on drug designing in adherence single antiviral agent targeting Mpro against all CoV-associated diseases. 

References    

Kanhed, A.M., Patel, D.V., Teli, D.M., Patel, N.R., Chhabria, M.T. and Yadav, M.R., 2021. Identification of potential Mpro inhibitors for the treatment of COVID-19 by using systematic virtual screening approach. Molecular diversity25(1), pp.383-401.

Rajpoot, S., Alagumuthu, M. and Baig, M.S., 2021. Dual targeting of 3clpro and Plpro of Sars-Cov-2: a novel structure-based design approach to treat Covid-19. Current research in structural biology3, pp.9-18.

Sacco, M.D., Ma, C., Lagarias, P., Gao, A., Townsend, J.A., Meng, X., Dube, P., Zhang, X., Hu, Y., Kitamura, N., Hurst, B., Tarbet, B., Marty, M.T., Kolocouris, A., Xiang, Y., Chen, Y. and Wang, J., 2020. Structure and inhibition of the SARS-CoV-2 main protease reveals strategy for developing dual inhibitors against Mpro and cathepsin L. bioRxivp.2020.07.27.223727.

 Zhang, L. and Guo, H., 2020. Biomarkers of COVID-19 and technologies to combat SARS-CoV-2. Advances in biomarker sciences and technology.

Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., Becker, S., Rox, K. and Hilgenfeld, R., 2020. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science, 368(6489), p.eabb3405.

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