A community effort to discover small molecule SARS-CoV-2 inhibitors
Authors: Schimunek Johannes , Seidl Philipp , Elez Katarina , Hempel Tim , Le Tuan , Noé Frank , Olsson Simon , Raich Lluís , Winter Robin , Gokcan Hatice , Gusev Filipp , Gutkin Evgeny M. , Isayev Olexandr , Kurnikova Maria G. , Narangoda Chamali H. , Zubatyuk Roman , Bosko Ivan P. , Furs Konstantin V. , Karpenko Anna D. , Kornoushenko Yury V. , Shuldau Mikita , Yushkevich Artsemi , Benabderrahmane Mohammed B. , Bousquet-Melou Patrick , Bureau Ronan , Charton Beatrice , Cirou Bertrand C. , Gil Gérard , Allen William J. , Sirimulla Suman , Watowich Stanley , Antonopoulos Nick A. , Epitropakis Nikolaos E. , Krasoulis Agamemnon K. , Pitsikalis Vassilis P. , Theodorakis Stavros T. , Kozlovskii Igor , Maliutin Anton , Medvedev Alexander , Popov Petr , Zaretckii Mark , Eghbal-zadeh Hamid , Halmich Christina , Hochreiter Sepp , Mayr Andreas , Ruch Peter , Widrich Michael , Berenger Francois , Kumar Ashutosh , Yamanishi Yoshihiro , Zhang Kam Y.J. , Bengio Emmanuel , Bengio Yoshua , Jain Moksh J. , Korablyov Maksym , Liu Cheng-Hao , Marcou Gilles , Glaab Enrico , Barnsley Kelly , Iyengar Suhasini M. , Ondrechen Mary Jo , Haupt V. Joachim , Kaiser Florian , Schroeder Michael , Pugliese Luisa , Albani Simone , Athanasiou Christina , Beccari Andrea , Carloni Paolo , D'Arrigo Giulia , Gianquinto Eleonora , Goßen Jonas , Hanke Anton , Joseph Benjamin P. , Kokh Daria B. , Kovachka Sandra , Manelfi Candida , Mukherjee Goutam , Muñiz-Chicharro Abraham , Musiani Francesco , Nunes-Alves Ariane , Paiardi Giulia , Rossetti Giulia , Sadiq S. Kashif , Spyrakis Francesca , Talarico Carmine , Tsengenes Alexandros , Wade Rebecca C. , Copeland Conner , Gaiser Jeremiah , Olson Daniel R. , Roy Amitava , Venkatraman Vishwesh , Wheeler Travis J. , Arthanari Haribabu , Blaschitz Klara , Cespugli Marco , Durmaz Vedat , Fackeldey Konstantin , Fischer Patrick D. , Gorgulla Christoph , Gruber Christian , Gruber Karl , Hetmann Michael , Kinney Jamie E. , Padmanabha Das Krishna M. , Pandita Shreya , Singh Amit , Steinkellner Georg , Tesseyre Guilhem , Wagner Gerhard , Wang Zi-Fu , Yust Ryan J. , Druzhilovskiy Dmitry S. , Filimonov Dmitry A. , Pogodin Pavel V. , Poroikov Vladimir , Rudik Anastassia V. , Stolbov Leonid A. , Veselovsky Alexander V. , De Rosa Maria , De Simone Giada , Gulotta Maria R. , Lombino Jessica , Mekni Nedra , Perricone Ugo , Casini Arturo , Embree Amanda , Gordon D. Benjamin , Lei David , Pratt Katelin , Voigt Christopher A. , Chen Kuang-Yu , Jacob Yves , Krischuns Tim , Lafaye Pierre , Zettor Agnès , Rodríguez M. Luis , White Kris M. , Fearon Daren , Von Delft Frank , Walsh Martin A. , Horvath Dragos , Brooks III Charles L. , Falsafi Babak , Ford Bryan , García-Sastre Adolfo , Lee Sang Yup , Naffakh Nadia , Varnek Alexandre , Klambauer Günter , Hermans Thomas M. 
Published: April 2023

The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of a community effort, the “Billion molecules against Covid-19 challenge”, to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 potentially active molecules, which were subsequently ranked to find ‘consensus compounds’. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (Nsp12 domain), and (alpha) spike protein S. Overall, 27 potential inhibitors were experimentally confirmed by binding-, cleavage-, and/or viral suppression assays and are presented here. All results are freely available and can be taken further downstream without IP restrictions. Overall, we show the effectiveness of computational techniques, community efforts, and communication across research fields (i.e., protein expression and crystallography, in silico modeling, synthesis and biological assays) to accelerate the early phases of drug discovery.