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

Berta, D; Badaoui, M; Martino, SA; Buigues, PJ; Pisliakov, AV; Elghobashi-Meinhardt, N; Wells, G; ... Rosta, E; + view all (2021) Modelling the active SARS-CoV-2 helicase complex as a basis for structure-based inhibitor design. Chemical Science 10.1039/d1sc02775a. (In press). Green open access

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Abstract

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.

Type: Article
Title: Modelling the active SARS-CoV-2 helicase complex as a basis for structure-based inhibitor design
Open access status: An open access version is available from UCL Discovery
DOI: 10.1039/d1sc02775a
Publisher version: https://doi.org/10.1039/D1SC02775A
Language: English
Additional information: © Royal Society of Chemistry 2021. This article is Open Access (http://creativecommons.org/licenses/by/3.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Physics and Astronomy
URI: https://discovery.ucl.ac.uk/id/eprint/10135587
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