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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.
Afiliación
  • Gahbauer S; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158.
  • Correy GJ; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158.
  • Schuller M; Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
  • Ferla MP; Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • Doruk YU; National Institute for Health Research Oxford Biomedical Research Centre, Oxford OX4 2PG, UK.
  • Rachman M; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158.
  • Wu T; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158.
  • Diolaiti M; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158.
  • Wang S; Chemistry and Chemical Biology Graduate Program, University of California San Francisco, San Francisco, CA 94158.
  • Neitz RJ; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158.
  • Fearon D; Chemistry and Chemical Biology Graduate Program, University of California San Francisco, San Francisco, CA 94158.
  • Radchenko DS; Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, CA 94158.
  • Moroz YS; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.
  • Irwin JJ; Research Complex at Harwell Harwell Science and Innovation Campus, Didcot OX11 0FA, UK.
  • Renslo AR; Enamine Ltd., Kyiv 02094, Ukraine.
  • Taylor JC; Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine.
  • Gestwicki JE; Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine.
  • von Delft F; Chemspace, Kyiv 02094, Ukraine.
  • Ashworth A; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158.
  • Ahel I; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158.
  • Shoichet BK; Department of Pharmaceutical Chemistry and Small Molecule Discovery Center, University of California, San Francisco, CA 94158.
  • Fraser JS; Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Proc Natl Acad Sci U S A ; 120(2): e2212931120, 2023 01 10.
Article en En | MEDLINE | ID: mdl-36598939
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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: SARS-CoV-2 / COVID-19 Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: SARS-CoV-2 / COVID-19 Tipo de estudio: Diagnostic_studies / Screening_studies Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article