> Details

Boby, Melissa L.; Fearon, Daren; Ferla, Matteo; Filep, Mihajlo; Koekemoer, Lizbé; Robinson, Matthew C.; Chodera, John D.; Lee, Alpha A.; London, Nir; von Delft, Annette; von Delft, Frank; Achdout, Hagit; Aimon, Anthony; Alonzi, Dominic S.; Arbon, Robert; Aschenbrenner, Jasmin C.; Balcomb, Blake H.; Bar-David, Elad; Barr, Haim; Ben-Shmuel, Amir; Bennett, James; Bilenko, Vitaliy A.; Borden, Bruce; Boulet, Pascale; [...]

Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors

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  • Media type: E-Article
  • Title: Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
  • Contributor: Boby, Melissa L.; Fearon, Daren; Ferla, Matteo; Filep, Mihajlo; Koekemoer, Lizbé; Robinson, Matthew C.; Chodera, John D.; Lee, Alpha A.; London, Nir; von Delft, Annette; von Delft, Frank; Achdout, Hagit; Aimon, Anthony; Alonzi, Dominic S.; Arbon, Robert; Aschenbrenner, Jasmin C.; Balcomb, Blake H.; Bar-David, Elad; Barr, Haim; Ben-Shmuel, Amir; Bennett, James; Bilenko, Vitaliy A.; Borden, Bruce; Boulet, Pascale; [...]
  • imprint: American Association for the Advancement of Science (AAAS), 2023
  • Published in: Science
  • Language: English
  • DOI: 10.1126/science.abo7201
  • ISSN: 0036-8075; 1095-9203
  • Keywords: Multidisciplinary
  • Origination:
  • Footnote:
  • Description: <jats:p>We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (&gt;18,000 designs), crystallographic data (&gt;490 ligand-bound x-ray structures), assay data (&gt;10,000 measurements), and synthesized molecules (&gt;2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property–free knowledge base for future anticoronavirus drug discovery.</jats:p>