The COVID Moonshot Consortium None., Achdout H., Aimon A., Bar-David E., Barr H., Ben-Shmuel A., Bennett J., Bilenko V., Bilenko V., Boby M., Borden B., Bowman G., Brun J., BVNBS S., Calmiano M., Carbery A., Carney D., Cattermole E., Chang E., Chernyshenko E., Chodera J., Clyde A., Coffland J., Cohen G., Cole J., Contini A., Cox L., Cvitkovic M., Dias A., Donckers K., Dotson D., Douangamath A., Duberstein S., Dudgeon T., Dunnett L., Eastman P., Erez N., Eyermann C., Fairhead M., Fate G., Fearon D., Fedorov O., Ferla M., Fernandes R., Ferrins L., Foster R., Foster H., Gabizon R., Garcia-Sastre A., Gawriljuk V., Gehrtz P., Gileadi C., Giroud C., Glass W., Glen R., Glinert I., Godoy A., Gorichko M., Gorrie-Stone T., Griffen E., Hart SH., Heer J., Henry M., Hill M., Horrell S., Huliak V., Hurley MFD., Israely T., Jajack A., Jansen J., Jnoff E., Jochmans D., John T., Jonghe SD., Kantsadi A., Kenny P., Kiappes JL., Kinakh S., Koekemoer L., Kovar B., Krojer T., Lee A., Lefker B., Levy H., Logvinenko I., London N., Lukacik P., Macdonald HB., MacLean B., Malla T., Matviiuk T., McCorkindale W., McGovern B., Melamed S., Melnykov K., Michurin O., Mikolajek H., Milne B., Morris A., Morris G., Morwitzer MJ., Moustakas D., Nakamura A., Neto JB., Neyts J., Nguyen L., Noske G., Oleinikovas V., Oliva G., Overheul G., Owen D., Pai R., Pan J., Paran N., Perry B., Pingle M., Pinjari J., Politi B., Powell A., Psenak V., Puni R., Rangel V., Reddi R., Reid SP., Resnick E., Ripka EG., Robinson M., Robinson R., Rodriguez-Guerra J., Rosales R., Rufa D., Saar K., Saikatendu KS., Schofield C., Shafeev M., Shaikh A., Shi J., Shurrush K., Singh S., Sittner A., Skyner R., Smalley A., Smeets B., Smilova M., Solmesky L., Spencer J., Strain-Damerell C., Swamy V., Tamir H., Tennant R., Thompson W., Thompson A., Tomasio S., Tsurupa I., Tumber A., Vakonakis I., van Rij R., Vangeel L., Varghese F., Vaschetto M., Vitner E., Voelz V., Volkamer A., von Delft F., von Delft A., Walsh M., Ward W., Weatherall C., Weiss S., White K., Wild CF., Wittmann M., Wright N., Yahalom-Ronen Y., Zaidmann D., Zidane H., Zitzmann N.

The COVID-19 pandemic is a stark reminder that a barren global antiviral pipeline has grave humanitarian consequences. Future pandemics could be prevented by accessible, easily deployable broad-spectrum oral antivirals and open knowledge bases that derisk and accelerate novel antiviral discovery and development. Here, we report the results of the COVID Moonshot , a fully open-science structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a novel chemical scaffold that is differentiated from current clinical candidates in terms of toxicity, resistance, and pharmacokinetics liabilities, and developed it into noncovalent orally-bioavailable nanomolar inhibitors with clinical potential. Our approach leveraged crowdsourcing, high-throughput structural biology, machine learning, and exascale molecular simulations. In the process, we generated a detailed map of the structural plasticity of the main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. In a first for a structure-based drug discovery campaign, all compound designs (>18,000 designs), crystallographic data (>500 ligand-bound X-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2,400 compounds) for this campaign were shared rapidly and openly, creating a rich open and IP-free knowledgebase for future anti-coronavirus drug discovery.

Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics

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