Modelling the active SARS-CoV-2 helicase complex as a basis for structure-based inhibitor design

The RNA helicase (non-structural protein 13, NSP13) of SARS-CoV-2 is essential for viral replication, and it is highly conserved among the coronaviridae family, thus a prominent drug target to treat COVID-19. We present here structural models and dynamics of the helicase in complex with its native s...

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Bibliographic Details
Published in:Chemical science (Cambridge) 2021-10, Vol.12 (4), p.13492-1355
Main Authors: Berta, Dénes, Badaoui, Magd, Martino, Sam Alexander, Buigues, Pedro J, Pisliakov, Andrei V, Elghobashi-Meinhardt, Nadia, Wells, Geoff, Harris, Sarah A, Frezza, Elisa, Rosta, Edina
Format: Article
Language:English
Subjects:
Binding sites
Biochemistry, Molecular Biology
Chemical Sciences
Chemistry
Coronaviruses
COVID-19
Dynamic structural analysis
Homology
Life Sciences
Medicinal Chemistry
Microbiology and Parasitology
Molecular dynamics
Severe acute respiratory syndrome coronavirus 2
Structural Biology
Structural models
Substrates
Virology
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Summary:The RNA helicase (non-structural protein 13, NSP13) of SARS-CoV-2 is essential for viral replication, and it is highly conserved among the coronaviridae family, thus a prominent drug target to treat COVID-19. We present here structural models and dynamics of the helicase in complex with its native substrates based on thorough analysis of homologous sequences and existing experimental structures. We performed and analysed microseconds of molecular dynamics (MD) simulations, and our model provides valuable insights to the binding of the ATP and ssRNA at the atomic level. We identify the principal motions characterising the enzyme and highlight the effect of the natural substrates on this dynamics. Furthermore, allosteric binding sites are suggested by our pocket analysis. Our obtained structural and dynamical insights are important for subsequent studies of the catalytic function and for the development of specific inhibitors at our characterised binding pockets for this promising COVID-19 drug target. The RNA helicase (non-structural protein 13, NSP13) of SARS-CoV-2 is essential for viral replication, and it is highly conserved among the coronaviridae family, thus a prominent drug target to treat COVID-19.
ISSN:2041-6520
2041-6539
DOI:10.1039/d1sc02775a