The COVID-19 pandemic is really a stark reminder that a barren global antiviral pipeline has grave humanitarian consequences. Future pandemics could be prevented by accessible, quickly deployable broad-spectrum oral antivirals and open information bases that derisk and accelerate novel antiviral discovery and development. Here, we report the results with the COVID Moonshot, a totally open-science structure-enabled drug discovery campaign targeting the SARS-CoV-2 primary protease. We discovered a novel chemical scaffold that may be differentiated to current clinical candidates with regards to toxicity and pharmacokinetics liabilities, and created it into orally-bioavailable inhibitors with clinical prospective. Our method leverages crowdsourcing, high throughput structural biology, machine mastering, and exascale molecular simulations. Within the process, we generated a detailed map from the structural plasticity on the major protease, substantial structure-activity relationships for multiple chemotypes, and also a wealth of biochemical activity information. In a initial to get a structure-based drug discovery campaign, all compound styles (>18,000 designs), crystallographic information (>500 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign had been shared swiftly and openly, producing a wealthy open and IP-free knowledgebase for future anti-coronavirus drug discovery. 82409-02-7 structure 2-Bromo-5-(trifluoromethyl)thiazole Chemscene PMID:24423657