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Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2
The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9926234/ https://www.ncbi.nlm.nih.gov/pubmed/36598939 http://dx.doi.org/10.1073/pnas.2212931120 |
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author | Gahbauer, Stefan Correy, Galen J. Schuller, Marion Ferla, Matteo P. Doruk, Yagmur Umay Rachman, Moira Wu, Taiasean Diolaiti, Morgan Wang, Siyi Neitz, R. Jeffrey Fearon, Daren Radchenko, Dmytro S. Moroz, Yurii S. Irwin, John J. Renslo, Adam R. Taylor, Jenny C. Gestwicki, Jason E. von Delft, Frank Ashworth, Alan Ahel, Ivan Shoichet, Brian K. Fraser, James S. |
author_facet | Gahbauer, Stefan Correy, Galen J. Schuller, Marion Ferla, Matteo P. Doruk, Yagmur Umay Rachman, Moira Wu, Taiasean Diolaiti, Morgan Wang, Siyi Neitz, R. Jeffrey Fearon, Daren Radchenko, Dmytro S. Moroz, Yurii S. Irwin, John J. Renslo, Adam R. Taylor, Jenny C. Gestwicki, Jason E. von Delft, Frank Ashworth, Alan Ahel, Ivan Shoichet, Brian K. Fraser, James S. |
author_sort | Gahbauer, Stefan |
collection | PubMed |
description | The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic, there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high-resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 153 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1. |
format | Online Article Text |
id | pubmed-9926234 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-99262342023-02-15 Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2 Gahbauer, Stefan Correy, Galen J. Schuller, Marion Ferla, Matteo P. Doruk, Yagmur Umay Rachman, Moira Wu, Taiasean Diolaiti, Morgan Wang, Siyi Neitz, R. Jeffrey Fearon, Daren Radchenko, Dmytro S. Moroz, Yurii S. Irwin, John J. Renslo, Adam R. Taylor, Jenny C. Gestwicki, Jason E. von Delft, Frank Ashworth, Alan Ahel, Ivan Shoichet, Brian K. Fraser, James S. Proc Natl Acad Sci U S A Biological Sciences The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic, there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high-resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 153 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1. National Academy of Sciences 2023-01-04 2023-01-10 /pmc/articles/PMC9926234/ /pubmed/36598939 http://dx.doi.org/10.1073/pnas.2212931120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Gahbauer, Stefan Correy, Galen J. Schuller, Marion Ferla, Matteo P. Doruk, Yagmur Umay Rachman, Moira Wu, Taiasean Diolaiti, Morgan Wang, Siyi Neitz, R. Jeffrey Fearon, Daren Radchenko, Dmytro S. Moroz, Yurii S. Irwin, John J. Renslo, Adam R. Taylor, Jenny C. Gestwicki, Jason E. von Delft, Frank Ashworth, Alan Ahel, Ivan Shoichet, Brian K. Fraser, James S. Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2 |
title | Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2 |
title_full | Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2 |
title_fullStr | Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2 |
title_full_unstemmed | Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2 |
title_short | Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2 |
title_sort | iterative computational design and crystallographic screening identifies potent inhibitors targeting the nsp3 macrodomain of sars-cov-2 |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9926234/ https://www.ncbi.nlm.nih.gov/pubmed/36598939 http://dx.doi.org/10.1073/pnas.2212931120 |
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