Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
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 (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>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.
| Errataetall: |
CommentIn: Nat Rev Drug Discov. 2024 Jan;23(1):22. - PMID 38040790 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:382 |
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| Enthalten in: |
Science (New York, N.Y.) - 382(2023), 6671 vom: 10. Nov., Seite eabo7201 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Boby, Melissa L [VerfasserIn] |
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| Links: |
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| Themen: |
3C-like proteinase, SARS-CoV-2 |
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| Anmerkungen: |
Date Completed 30.11.2023 Date Revised 20.04.2024 published: Print-Electronic CommentIn: Nat Rev Drug Discov. 2024 Jan;23(1):22. - PMID 38040790 Citation Status MEDLINE |
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| doi: |
10.1126/science.abo7201 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a CommentIn: Nat Rev Drug Discov. 2024 Jan;23(1):22. - PMID 38040790 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>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 | ||
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