Allosteric Inhibition of the SARS‐CoV‐2 Main Protease: Insights from Mass Spectrometry Based Assays**

El‐Baba, Tarick J.; Lutomski, Corinne A.; Kantsadi, A.L.; Malla, Tika R.; John, Tobias; Mikhailov, Victor A.; Bolla, Jani Reddy; Schofield, Christopher J.; Zitzmann, Nicole; Vakonakis, Ioannis; Robinson, Carol V.

doi:10.1002/ange.202010316

Cited by 27 publications

(29 citation statements)

References 16 publications

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“…El-Baba et al, in their mass spectrometry based study for the investigation of allosteric inhibitor of M pro revealed binding of potential allosteric inhibitor x1187 at the binding site comprising residues Phe8, Met6, Gln127, Ser139, Asp295, Arg298, and Gln299. Gln127 being common to the mentioned studies and to our analysis may be considered as effective residue for allosteric inhibition thus depicting the accuracy of allosteric site selection in the present study (El-Baba et al 2020 ). Iftikhar et al in their in-silico study on inhibitors against three potential enzyme targets of SARS-CoV-2 reported Bagrosin as an allosteric inhibitor, binding with an energy of − 7.9 kcal/mol at an allosteric site lying close to the site reported in the present study, of SARS-CoV-2 proteinase with Lys5 as common interacting residue (Iftikhar et al 2020 ).…”

Section: Resultsmentioning

confidence: 67%

Factual insights of the allosteric inhibition mechanism of SARS-CoV-2 main protease by quercetin: an in silico analysis

Verma

Pandey

2021

3 Biotech

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SARS-CoV-2 main protease (M pro ) cleaves the viral polypeptide 1a and 1ab in a site-specific ((L-Q|(S, A, G)) manner and produce functional enzymes for mediating viral replication. Numerous studies have reported synthetic competitive inhibitors against this target enzyme but increase in substrate concentration often reduces the effectiveness of such inhibitors. Allosteric inhibition by natural compound can provide safe and effective treatment by alleviating this limitation. Present study deals with in silico allosteric inhibition analysis of quercetin, against SARS-CoV-2-M pro . Molecular docking of quercetin with M pro revealed consistent binding of quercetin at a site other than active site in multiple runs, with the highest binding energy of − 8.31 kcal/mol, forming 6 H-bonds with residues Gln127, Cys128, Lys137, Asp289 and Glu290. Molecular dynamic simulation of 50 ns revealed high stability of M pro -quercetin complex with RMSD values ranging from 0.1 to 0.25 nm. Moreover, native-M pro and M pro -quercetin complex conformations extracted at different time points from simulation trajectories were subjected to active site-specific docking with modelled substrate peptide (AVLQSGFR) by ZDOCK server. Results displayed site-specific cleavage of peptide when docked with native-M pro . While substrate peptide remained intact when docked with M pro -quercetin complex, also the binding energy of peptide reduced from 785 to 86 from 1 to 50 ns as quercetin induced alterations in the active site cavity reducing its affinity for the substrate. Further, no interactions were noticed between peptide and active site residues of M pro -quercetin complex conformations at 40 and 50 ns. Hence, quercetin displayed effective allosteric inhibition potential against SARS-CoV-2 M pro , and can be developed into an efficient treatment for COVID-19.

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Section: Resultsmentioning

confidence: 67%

Factual insights of the allosteric inhibition mechanism of SARS-CoV-2 main protease by quercetin: an in silico analysis

Verma

Pandey

2021

3 Biotech

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“…Work of Robinson and Vakonakis 193 focused on the protease M encoded by the SARS-COV-2 RNA genome. Its role is to process several of the virus structural proteins.…”

Section: Mass Spectrometry In the Era Of Covid-19mentioning

confidence: 99%

Mass Spectrometry-Based Structural Virology

et al. 2020

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“…Elastic network model analysis, binding site predictions followed by MD simulations has been used to predict the allosteric sites on the main protease protein [ 118 , 119 ]. The identification of allosteric binding sites on the main protease has also been identified by mass spectrometry based studies [ 120 ]. The binding of small molecules on these sites is proposed to reduce the rate of substrate processing and dimerization.…”

Section: Overview Of Some Of the Applications Of Structural Bioinformmentioning

confidence: 99%

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

Waman¹,

Sen²,

Váradi³

et al. 2020

Briefings in Bioinformatics

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SARS-CoV-2 is the causative agent of COVID-19, the ongoing global pandemic. It has posed a worldwide challenge to human health as no effective treatment is currently available to combat the disease. Its severity has led to unprecedented collaborative initiatives for therapeutic solutions against COVID-19. Studies resorting to structure-based drug design for COVID-19 are plethoric and show good promise. Structural biology provides key insights into 3D structures, critical residues/mutations in SARS-CoV-2 proteins, implicated in infectivity, molecular recognition and susceptibility to a broad range of host species. The detailed understanding of viral proteins and their complexes with host receptors and candidate epitope/lead compounds is the key to developing a structure-guided therapeutic design. Since the discovery of SARS-CoV-2, several structures of its proteins have been determined experimentally at an unprecedented speed and deposited in the Protein Data Bank. Further, specialized structural bioinformatics tools and resources have been developed for theoretical models, data on protein dynamics from computer simulations, impact of variants/mutations and molecular therapeutics. Here, we provide an overview of ongoing efforts on developing structural bioinformatics tools and resources for COVID-19 research. We also discuss the impact of these resources and structure-based studies, to understand various aspects of SARS-CoV-2 infection and therapeutic development. These include (i) understanding differences between SARS-CoV-2 and SARS-CoV, leading to increased infectivity of SARS-CoV-2, (ii) deciphering key residues in the SARS-CoV-2 involved in receptor–antibody recognition, (iii) analysis of variants in host proteins that affect host susceptibility to infection and (iv) analyses facilitating structure-based drug and vaccine design against SARS-CoV-2.

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Allosteric Inhibition of the SARS‐CoV‐2 Main Protease: Insights from Mass Spectrometry Based Assays**

Abstract: Supporting information for this article is given via a link at the end of the document.

Cited by 27 publications

References 16 publications

Factual insights of the allosteric inhibition mechanism of SARS-CoV-2 main protease by quercetin: an in silico analysis

Factual insights of the allosteric inhibition mechanism of SARS-CoV-2 main protease by quercetin: an in silico analysis

Mass Spectrometry-Based Structural Virology

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

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