Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography

Article Article scientifique Article Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography eng 2022-11-22 2022-11-22 author Borsatto Alberto 0000-0002-8889-6491 941078 Section des sciences pharmaceutiques (FARMA) author Akkad Obaeda 824384 author Galdadas Yiannis 0000-0003-2136-9723 945699 Section des sciences pharmaceutiques (FARMA) author Ma Shumeng author Damfo Shymaa 0000-0002-2070-7770 author Haider Shozeb 0000-0003-2650-2925 author Kozielski Frank 0000-0001-6096-9102 author Estarellas Carolina 0000-0002-0944-9053 author Gervasio Francesco Luigi 0000-0003-4831-5039 931636 Section des sciences pharmaceutiques (FARMA) e81167 10.7554/eLife.81167 36412088 2050-084X PMC9681203 https://elifesciences.org/articles/81167 <p> Non-structural protein 1 (Nsp1) is a main pathogenicity factor of α - and β - coronaviruses. Nsp1 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppresses the host gene expression by sterically blocking 40S host ribosomal subunits and promoting host mRNA degradation. This mechanism leads to the downregulation of the translation-mediated innate immune response in host cells, ultimately mediating the observed immune evasion capabilities of SARS-CoV-2. Here, by combining extensive molecular dynamics simulations, fragment screening and crystallography, we reveal druggable pockets in Nsp1. Structural and computational solvent mapping analyses indicate the partial crypticity of these newly discovered and druggable binding sites. The results of fragment-based screening via X-ray crystallography confirm the druggability of the major pocket of Nsp1. Finally, we show how the targeting of this pocket could disrupt the Nsp1-mRNA complex and open a novel avenue to design new inhibitors for other Nsp1s present in homologous β - coronaviruses. </p> SARS-CoV-2 X-ray crystallography Cryptic pockets Drug discovery Molecular biophysics Molecular dynamics None Structural biology Dewey 615 Swiss National Supercomputing Centre s1107 Engineering and Physical Sciences Research Council EP/P011306/1 Swiss National Science Foundation Understanding and Modelling Cryptic Binding Pockets for Biology and Drug Discovery 204795 CH Projects Swiss National Science Foundation ABCD Antibodies: Recombinant antibodies for research 203628 CH Programmes 31 Section des sciences pharmaceutiques 17 false 1362 Modélisation biomoléculaire et pharmaceutique https://www.rcsb.org/structure/8A4Y eLife 11 67a29380-2edf-4b6b-9e0d-757d4535ac1c Article (Published version) Public Article-scientifique-from-crossref.pdf 5971605 application/pdf CC BY-4.0 2d9f33b2bd4f6de0b92d1c0501fa4e11ea1c160d5dbb51a21b4a66088bc7d67e openAccess Faculté des sciences / Section des sciences pharmaceutiques

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Understanding Cryptic Binding Pockets for Biology and Drug Discovery		2024	195	11
Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography	eLife	2022	90	54

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