Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors

Perez-Lemus, Gustavo R.; Menéndez, Cintia A.; Alvarado, Walter; Byléhn, Fabian; de Pablo, Juan J.

doi:10.1126/sciadv.abj4526

Title: Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors

Journal Article · 06 January 2022 · Science Advances

DOI: https://doi.org/10.1126/sciadv.abj4526 · OSTI ID:2469992

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Univ. of Chicago, IL (United States)
Univ. of Chicago, IL (United States); Universidad Nacional del Sur (UNS) (Argentina)
Argonne National Laboratory (ANL), Argonne, IL (United States); Univ. of Chicago, IL (United States)

To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Science Foundation (NSF); USDOD; USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2469992

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 1 Vol. 8; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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