Open Science Discovery of Potent Non-Covalent SARS-CoV-2 Main Protease Inhibitors
Achdout H., Aimon A., Alonzi DS., Arbon R., Bar-David E., Barr H., Ben-Shmuel A., Bennett J., Bilenko VA., Bilenko VA., Boby ML., Borden B., Boulet P., Bowman GR., Brun J., Brwewitz L., Bvnbs S., Calmiano M., Carbery A., Carney D., Cattermole E., Chang E., Chernyshenko E., Chodera JD., Clyde A., Coffland JE., Cohen G., Cole J., Contini A., Cox L., Croll TI., Cvitkovic M., Dias A., Donckers K., Dotson DL., Douangamath A., Duberstein S., Dudgeon T., Dunnett L., Eastman PK., Erez N., Eyermann CJ., Fairhead M., Fate G., Fearon D., Fedorov O., Ferla M., Fernandes RS., Ferrins L., Filep M., Foster R., Foster H., Fraisse L., Gabizon R., Garcia-Sastre A., Gawriljuk VO., Gehrtz P., Gileadi C., Giroud C., Glass WG., Glen R., Glinert I., Godoy AS., Gorichko M., Gorrie-Stone T., Griffen EJ., Hahn S., Haneef A., Hart SH., Heer J., Henry M., Hill M., Horrell S., Huang QY., Huliak VD., Huliak VD., Hurley MFD., Israely T., Jajack A., Jansen J., Jnoff E., Jochmans D., John T., Jonghe SD., Kaminow B., Kang L., Kantsadi AL., Kenny PW., Kiappes JL., Kinakh SO., Kinakh SO., Koekemoer L., Kovar B., Krojer T., La V., Lee AA., Lefker BA., Levy H., Logvinenko IG., Logvinenko IG., London N., Lukacik P., Macdonald HB., MacLean EM., Makower LL., Malla TR., Matviiuk T., McCorkindale W., McGovern BL., Melamed S., Melnykov KP., Melnykov KP., Michurin O., Miesen P., Mikolajek H., Milne BF., Minh D., Morris A., Morris GM., Morwitzer MJ., Moustakas D., Mowbray C., Nakamura AM., Neto JB., Neyts J., Nguyen L., Noske GD., Oleinikovas V., Oliva G., Overheul GJ., Owen D., Pai R., Pan J., Paran N., Payne A., Perry B., Pingle M., Pinjari J., Politi B., Powell A., Psenak V., Pulido I., Puni R., Rangel VL., Reddi RN., Rees P., Reid SP., Reid L., Resnick E., Ripka EG., Robinson MC., Robinson RP., Rodriguez-Guerra J., Rosales R., Rufa DA., Saar K., Saikatendu KS., Salah E., Schaller D., Scheen J., Schiffer CA., Schofield C., Shafeev M., Shaikh A., Shaqra AM., Shi J., Shurrush K., Singh S., Sittner A., Sjo 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., Tomasio S., Tomlinson C., Tsurupa IS., Tsurupa IS., Tumber A., Vakonakis I., van Rij RP., Vangeel L., Varghese FS., Vaschetto M., Vitner EB., Voelz V., Volkamer A., von Delft F., von Delft A., Walsh M., 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.
AbstractThe COVID-19 pandemic was a stark reminder that a barren global antiviral pipeline has grave humanitarian consequences. Pandemics could be prevented in principle by accessible, easily deployable broad-spectrum oral antivirals. Here we report the results of theCOVID Moonshot, a fully open-science, crowd sourced, structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. We discovered a novel chemical series that is differentiated from current Mpro inhibitors in that it maintains a new non-covalent, non-peptidic scaffold with nanomolar potency. Our approach leveraged crowdsourcing, high-throughput structural biology, machine learning, and exascale molecular simulations and high-throughput chemistry. In the process, 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. In a first for a structure-based drug discovery campaign, all compound designs (>18,000 designs), crystallographic data (>840 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.