Whole-genome sequence analysis and homology modelling of the main protease and non-structural protein 3 of SARS-CoV-2 reveal an aza-peptide and a lead inhibitor with possible antiviral properties

Shanker, Arun K.; Bhanu, Divya; Alluri, Anjani; Gupta, Samriddhi

doi:10.1039/d0nj00974a

Cited by 15 publications

(12 citation statements)

References 39 publications

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“…To better understand the molecular flexibility of RmSBP, we believe that the equilibrium molecular dynamics simulations at growth temperatures are definitely worthwhile. Of note, RmSBP shows sequence similarity of 20% with the ORF1ab polyprotein of SARS-CoV-2 (strain SARS-CoV-2_HKU-SZ-001_2020), and was, therefore, recently used as a template for modeling structures [ 21 ]. Although the sequence similarity of amino acids is not high between RmSBP and ORF1ab polyprotein in SARS-CoV-2, our structural results for RmSBP will help to understand the model structure of ORF1ab of SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

Structural Flexibility of Peripheral Loops and Extended C-terminal Domain of Short Length Substrate Binding Protein from Rhodothermus marinus

Bae

Kim

et al. 2021

Protein J

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Substrate binding proteins (SBPs) bind to specific ligands in the periplasmic regions of cells and then bind to membrane proteins to participate in transport or signal transduction. Typically, SBPs consist of two α/β domains and recognize the substrate by a flexible hinge region between the two domains. Conversely, the short-length SBPs are often observed in protein databases, which are located around methyl-accepting chemotaxis protein genes. We previously determined the crystal structure of Rhodothermus marinus SBP (named as RmSBP), consisting of a single α/β domain; however, the substrate recognition mechanism is still unclear. To better understand the functions of short length RmSBP, we performed a comprehensive study, involving comparative structure analysis, computational substrate docking, and X-ray crystallographic data. RmSBP shares a high level of similarity in the α/β domain region with other SBPs, but it has a distinct topology in the C-terminal domain. The substrate binding model suggested that conformational changes in the peripheral region of RmSBP was required to recognize the substrate. We determined the crystal structures of RmSBP at pH 5.5, 6.0, and 7.5. RmSBP showed structural flexibility in the β1–α2 loop, β5–β6 loop, and extended C-terminal domains, based on the electron density map and temperature B-factor analysis. These results provide information that will further our understanding on the functions of the short length SBP. Supplementary Information The online version contains supplementary material available at 10.1007/s10930-021-09970-z.

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Section: Discussionmentioning

confidence: 99%

Structural Flexibility of Peripheral Loops and Extended C-terminal Domain of Short Length Substrate Binding Protein from Rhodothermus marinus

Bae

Kim

et al. 2021

Protein J

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“…The proteases of novel coronavirus share high percentage of sequence and structure similarity with SARS coronavirus which has the main role in the processing of viral polyprotein. These proteins perform stripping ubiquitin to help in evading immune response of the host (Shanker et al., 2020 ). Small molecules and drug inhibitors can be designed to block the cascade signaling pathways to protect the host system.…”

Section: Introductionmentioning

confidence: 99%

Screening of phytochemical compounds of Tinospora cordifolia for their inhibitory activity on SARS-CoV-2: an in silico study

Krupanidhi

Peele

Venkateswarulu

et al. 2020

Journal of Biomolecular Structure and Dynamics

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In the present study, we explored phytochemical constituents of Tinospora cordifolia in terms of its binding affinity targeting the active site pocket of the main protease (3CL pro) of SARS-CoV-2 using molecular docking study and assessed the stability of top docking complex of tinosponone and 3CL pro using molecular dynamics simulations with GROMACS 2020.2 version. Out of 11 curated screened compounds, we found the significant docking score for tinosponone, xanosporic acid, cardiofolioside B, tembetarine and berberine in Tinospora cordifolia. Based on the findings of the docking study, it was confirmed that tinosponone is the potent inhibitor of main protease of SARS-CoV-2 with the best binding affinity of À7.7 kcal/mol. Further, ADME along with toxicity analysis was studied to predict the pharmacokinetics and drug-likeness properties of five top hits compounds. The molecular dynamics simulation analysis confirmed the stability of tinosponone and 3CL pro complex with a random mean square deviation (RMSD) value of 0.1 nm. The computer-aided drug design approach proved that the compound tinosponone from T. cordifolia is a potent inhibitor of 3CL main protease of SARS-CoV-2. Further, the in vitro and in vivo-based testing will be required to confirm its inhibitory effect on SARS-CoV-2.

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“…This is crucial for designing new drugs. An example to this is the study by Shankar et al which suggested two ligands that can possibly be developed into antivirals against SARS-CoV-2, the first (an aza-peptide epoxide) can be used to irreversibly inhibit viral protease and the second as a viral replication inhibitor [ 60 ]. Another study used computer-aided drug design to identify a mechanism-based inhibitor of SARS-CoV-2 Mpro and screened more than 10,000 compounds for their ability to inhibit this protease [ 63 ].…”

Section: Treatment and Drug Discoverymentioning

confidence: 99%

“…It was also shown to antagonize host innate immunity. [ 47 , 59 , 60 ] nsp4 500 aa (residues K2764 – Q3263) A multipass membrane protein responsible for membrane rearrangement. It interacts with nsp3 and 6 to form double membrane vesicles (DMV).…”

Section: Introductionmentioning

confidence: 99%

“…Putatively stabilizes nascent nucleic acid during replication or transcription protecting it from nucleases. [ 47 , 60 , 62 , 65 ] nsp10 139 aa (residues A4254 – Q4392) A small protein believed to act as a multifunctional cofactor. In replication it interacts with nsp14 involved in replication fidelity and also interacts with nsp16.…”

Section: Introductionmentioning

confidence: 99%

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Latest updates on SARS-CoV-2 genomic characterization, drug, and vaccine development; a comprehensive bioinformatics review

Sakr

Elsayed

El-Housseiny

2021

Microbial Pathogenesis

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Amid the COVID-19 outbreak, several bioinformatic analyses have been conducted on SARS-CoV-2 virus genome. Numerous studies rushed to fill the gap about this novel virus. Comparison with other related sequences, structural predictions of the produced proteins, determination of variations in amino acid residues and depiction of possible drug and vaccine targets have been the focus of scientific research from the beginning of this year. In addition to discussing the viral taxonomy, clinical features, life cycle, and genome organization, this review will focus on the recent updates in genome and viral proteins characterization and potential therapeutic and vaccine candidates developed so far. Comparative studies with related genomes and proteins provide understanding for the viral molecular mechanisms and suggest targets for therapeutics and vaccinology trials to stop the escalation of this new virus. This pandemic, with its resulting social and economic afflictions, will definitely have significant marks on our lives in the following years.

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Whole-genome sequence analysis and homology modelling of the main protease and non-structural protein 3 of SARS-CoV-2 reveal an aza-peptide and a lead inhibitor with possible antiviral properties

Abstract: SARS-CoV-2 3CLpro shows homology in binding to an aza-peptide epoxide (APE) known for the irreversible inhibition of main peptidase in SARS-CoV.

Cited by 15 publications

References 39 publications

Structural Flexibility of Peripheral Loops and Extended C-terminal Domain of Short Length Substrate Binding Protein from Rhodothermus marinus

Structural Flexibility of Peripheral Loops and Extended C-terminal Domain of Short Length Substrate Binding Protein from Rhodothermus marinus

Screening of phytochemical compounds of Tinospora cordifolia for their inhibitory activity on SARS-CoV-2: an in silico study

Latest updates on SARS-CoV-2 genomic characterization, drug, and vaccine development; a comprehensive bioinformatics review

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