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

Achdout, Hagit; Aimon, Anthony; Bar-David, Elad; Barr, Haim; Ben-Shmuel, Amir; Bennett, James; Boby, Melissa L.; Borden, Bruce; Bowman, Gregory R.; Brun, Juliane; BVNBS, Sarma; Calmiano, Mark; Carbery, Anna; Cattermole, Emma; Chernyshenko, Eugene; Chodera, John D.; Clyde, Austin; Coffland, Joseph E.; Cohen, Galit; Cole, Jason; Contini, Alessandro; Cox, Lisa; Cvitkovic, Milan; Dias, Alex; Donckers, Kim; Dotson, David L.; Douangamath, Alice; Duberstein, Shirly; Dudgeon, Tim; Dunnett, Louise; Eastman, Peter K.; Erez, Noam; Eyermann, Charles J.; Fairhead, Mike; Fate, Gwen; Fearon, Daren; Fedorov, Oleg; Ferla, Matteo; Fernandes, Rafaela S.; Ferrins, Lori; Foster, Richard; Foster, Holly; Gabizon, Ronen; Garcia-Sastre, Adolfo; Gawriljuk, Victor O.; Gehrtz, Paul; Gileadi, Carina; Giroud, Charline; Glass, William G.; Glen, Robert; Glinert, Itai; Godoy, Andre S.; Gorichko, Marian; Gorrie-Stone, Tyler; Griffen, Ed J.; Hart, Storm Hassell; Heer, Jag; Henry, Michael; Hill, Michelle; Horrell, Sam; Hurley, Matthew F.D.; Israely, Tomer; Jajack, Andrew; Jnoff, Eric; Jochmans, Dirk; John, Tobias; Jonghe, Steven De; Kantsadi, Anastassia L.; Kenny, Peter W.; Kiappes, J. L.; Koekemoer, Lizbe; Kovar, Boris; Krojer, Tobias; Lee, Alpha A.; Lefker, Bruce A.; Levy, Haim; London, Nir; Lukacik, Petra; Macdonald, Hannah Bruce; MacLean, Beth; Malla, Tika R.; Matviiuk, Tatiana; McCorkindale, Willam; McGovern, Briana L.; Melamed, Sharon; Michurin, Oleg; Mikolajek, Halina; Milne, Bruce F.; Morris, Aaron; Morris, Garrett M.; Morwitzer, Melody Jane; Moustakas, Demetri; Nakamura, Aline M.; Neto, Jose Brandao; Neyts, Johan; Nguyen, Luong; Noske, Gabriela D.; Oleinikovas, Vladas; Oliva, Glaucius; Overheul, Gijs J.; Owen, David; Psenak, Vladimir; Pai, Ruby; Pan, Jin; Paran, Nir; Perry, Benjamin; Pingle, Maneesh; Pinjari, Jakir; Politi, Boaz; Powell, Ailsa; Puni, Reut; Rangel, Victor L.; Reddi, Rambabu N.; Reid, St Patrick; Resnick, Efrat; Ripka, Emily Grace; Robinson, Matthew C.; Robinson, Ralph P.; Rodriguez-Guerra, Jaime; Rosales, Romel; Rufa, Dominic; Schofield, Chris; Shafeev, Mikhail; Shaikh, Aarif; Shi, Jiye; Shurrush, Khriesto; Singh, Sukrit; Sittner, Assa; Skyner, Rachael; Smalley, Adam; Smilova, Mihaela D.; Solmesky, Leonardo J.; Spencer, John; Strain-Damerell, Claire; Swamy, Vishwanath; Tamir, Hadas; Tennant, Rachael; Thompson, Warren; Thompson, Andrew; Thompson, Warren; Tomasio, Susana; Tumber, Anthony; Vakonakis, Ioannis; van Rij, Ronald P.; Vangeel, Laura; Varghese, Finny S.; Vaschetto, Mariana; Vitner, Einat B.; Voelz, Vincent; Volkamer, Andrea; von Delft, Frank; von Delft, Annette; Walsh, Martin; Ward, Walter; Weatherall, Charlie; Weiss, Shay; White, Kris M.; Wild, Conor Francis; Wittmann, Matthew; Wright, Nathan; Yahalom-Ronen, Yfat; Zaidmann, Daniel; Zidane, Hadeer; Zitzmann, Nicole

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 to current clinical candidates in terms of toxicity and pharmacokinetics liabilities, and developed it into orally-bioavailable inhibitors with clinical potential. Our approach leverages 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.