Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors.
Boby ML., Fearon D., Ferla M., Filep M., Koekemoer L., Robinson MC., COVID Moonshot Consortium‡ None., Chodera JD., Lee AA., London N., von Delft A., von Delft F., Achdout H., Aimon A., Alonzi DS., Arbon R., Aschenbrenner JC., Balcomb BH., Bar-David E., Barr H., Ben-Shmuel A., Bennett J., Bilenko VA., Borden B., Boulet P., Bowman GR., Brewitz L., Brun J., Bvnbs S., Calmiano M., Carbery A., Carney DW., Cattermole E., Chang E., Chernyshenko E., Clyde A., Coffland JE., Cohen G., Cole JC., Contini A., Cox L., Croll TI., Cvitkovic M., De Jonghe S., Dias A., Donckers K., Dotson DL., Douangamath A., Duberstein S., Dudgeon T., Dunnett LE., Eastman P., Erez N., Eyermann CJ., Fairhead M., Fate G., Fedorov O., Fernandes RS., Ferrins L., Foster R., Foster H., Fraisse L., Gabizon R., García-Sastre A., Gawriljuk VO., Gehrtz P., Gileadi C., Giroud C., Glass WG., Glen RC., Glinert I., Godoy AS., Gorichko M., Gorrie-Stone T., Griffen EJ., Haneef A., Hassell Hart S., Heer J., Henry M., Hill M., Horrell S., Huang QYJ., Huliak VD., Hurley MFD., Israely T., Jajack A., Jansen J., Jnoff E., Jochmans D., John T., Kaminow B., Kang L., Kantsadi AL., Kenny PW., Kiappes JL., Kinakh SO., Kovar B., Krojer T., La VNT., Laghnimi-Hahn S., Lefker BA., Levy H., Lithgo RM., Logvinenko IG., Lukacik P., Macdonald HB., MacLean EM., Makower LL., Malla TR., Marples PG., Matviiuk T., McCorkindale W., McGovern BL., Melamed S., Melnykov KP., Michurin O., Miesen P., Mikolajek H., Milne BF., Minh D., Morris A., Morris GM., Morwitzer MJ., Moustakas D., Mowbray CE., Nakamura AM., Neto JB., Neyts J., Nguyen L., Noske GD., Oleinikovas V., Oliva G., Overheul GJ., Owen CD., Pai R., Pan J., Paran N., Payne AM., Perry B., Pingle M., Pinjari J., Politi B., Powell A., Pšenák V., Pulido I., Puni R., Rangel VL., Reddi RN., Rees P., Reid SP., Reid L., Resnick E., Ripka EG., Robinson RP., Rodriguez-Guerra J., Rosales R., Rufa DA., Saar K., Saikatendu KS., Salah E., Schaller D., Scheen J., Schiffer CA., Schofield CJ., Shafeev M., Shaikh A., Shaqra AM., Shi J., Shurrush K., Singh S., Sittner A., Sjö P., Skyner R., Smalley A., Smeets B., Smilova MD., Solmesky LJ., Spencer J., Strain-Damerell C., Swamy V., Tamir H., Taylor JC., Tennant RE., Thompson W., Thompson A., Tomásio S., Tomlinson CWE., Tsurupa IS., Tumber A., Vakonakis I., van Rij RP., Vangeel L., Varghese FS., Vaschetto M., Vitner EB., Voelz V., Volkamer A., Walsh MA., Ward W., Weatherall C., Weiss S., White KM., Wild CF., Witt KD., Wittmann M., Wright N., Yahalom-Ronen Y., Yilmaz NK., Zaidmann D., Zhang I., Zidane H., Zitzmann N., Zvornicanin SN.
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.