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

• 成果类型: Article
• 署名作者: Boby, Melissa L.; Fearon, Daren; Ferla, Matteo; Filep, Mihajlo; Koekemoer, Lizbe; Robinson, Matthew C.; Chodera, John D.; Lee, Alpha A.; London, Nir; von Delft, Annette; von Delft, Frank
• 署名单位: Cornell University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Diamond Light Source; University of Oxford; Weizmann Institute of Science; University of Oxford; University of Oxford; University of Johannesburg
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12496
• DOI: 10.1126/science.abo7201
• 发表日期: 2023-11-10
• 关键词: coronavirus; integration; parameters; SARS

摘要

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.