Peer-Reviewed Publication
J Chem Inf Model2026;66(3):1566-1581.February 9, 2026Journal Article
CACHE Challenge #3: Targeting the Nsp3 Macrodomain of SARS-CoV-2.
Oleksandra Herasymenko1, Madhushika Silva1, Galen J Correy2, Abd Al-Aziz A Abu-Saleh3,4, Suzanne Ackloo1, Cheryl Arrowsmith1,5,6, Alan Ashworth7, Fuqiang Ban8, Hartmut Beck9, Kevin P Bishop10,11, Hugo J Bohórquez10,11, Albina Bolotokova1, Marko Breznik12, Irene Chau1, Yu Chen12, Artem Cherkasov13, Wim Dehaen14,15, Dennis Della Corte16, Katrin Denzinger12, Niklas P Doering12, Kristina Edfeldt17, Aled Edwards1, Darren Fayne18,19, Francesco Gentile20,21, Elisa Gibson1, Ozan Gokdemir22,23, Anders Gunnarsson24, Judith Günther25, John J Irwin26, Jan Halborg Jensen27, Rachel J Harding1,6,28,29, Alexander Hillisch30, Laurent Hoffer10,11, Anders Hogner31, Ashley Hutchinson1, Shubhangi Kandwal18,19,32,33, Andrea Karlova34, Kushal Koirala35, Sergei Kotelnikov36, Dima Kozakov36, Juyong Lee37,38,39, Soowon Lee38, Uta Lessel40, Sijie Liu12, Xuefeng Liu22,23, Peter Loppnau1, Jens Meiler41,42,43, Rocco Moretti44, Yurii S Moroz45, Charuvaka Muvva46, Tudor I Oprea47, Brooks Paige48, Amit Pandit12,49, Keunwan Park46, Gennady Poda10,11,28, Mykola V Protopopov45, Vera Pütter50, Rahul Ravichandran20, Didier Rognan51, Edina Rosta52, Yogesh Sabnis53, Thomas Scott44, Almagul Seitova1, Purshotam Sharma3,4, François Sindt51, Minghu Song54, Casper Steinmann55, Rick Stevens22,23, Valerij Talagayev12, Valentyna V Tararina56, Olga Tarkhanova42, Damon Tingey16, John F Trant3,4,57, Dakota Treleaven58, Alexander Tropsha35, Patrick Walters59, Jude Wells34, Yvonne Westermaier60, Gerhard Wolber12, Lars Wortmann61, Shuangjia Zheng62, James S Fraser2, Matthieu Schapira1,6,29
1Structural Genomics Consortium, University Health Network, Toronto, Ontario M5G 2C4, Canada.
2Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94158, United States.
3Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
4Binary Star Research Services, LaSalle, Ontario N9J 3X8, Canada.
5Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
6Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2C4, Canada.
7Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, United States.
8Vancouver Prostate Centre, 2660 Oak Street, Vancouver, British Columbia V6H3Z6, Canada.
9Bayer AG, Drug Discovery Sciences, Wuppertal 42113, Germany.
10Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
11QuAccel, Toronto, Ontario M4M 1L8, Canada.
12Molecular Design Group, Institute of Pharmacy, Department of Biology, Chemistry & Pharmacy, Freie Universitaet Berlin, Koenigin-Luisestr. 2+4, Berlin 14195, Germany.
13University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
14CZ-OPENSCREEN, Department of Informatics and Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology Prague, Technická 5, 16 628 Prague 6, Czech Republic.
15Department of Organic Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology Prague, Technická 5, 16 628 Prague 6, Czech Republic.
16Department of Physics and Astronomy, Brigham Young University, Provo 84602, Utah.
17Structural Genomics Consortium, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm 171 76, Sweden.
18DCU Life Sciences Institute, Dublin City University, Dublin D09 DXA0, Ireland.
19Molecular Design Group, School of Chemical Sciences, Dublin City University, Glasnevin, Dublin D09 V209, Ireland.
20Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.
21Ottawa Institute of Systems Biology, Ottawa, Ontario K1H 8M5, Canada.
22University of Chicago, Chicago, Illinois 60637, United States.
23Argonne National Laboratory, Lemont, Illinois 60439, United States.
24Protein, Structure and Biophysics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43150, Sweden.
25Bayer AG, Drug Discovery Sciences, Berlin 13353, Germany.
26Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 Fourth St, San Francisco, California 94158-2330, United States.
27Department of Chemistry, University of Copenhagen, 1353 Copenhagen, Denmark.
28Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
29Department of Pharmacology & Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
30UCB BioSciences GmbH, Rolf-Schwarz-Schütte-Platz 1, 40789 Monheim am Rhein, Germany.
31Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43150, Sweden.
32Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2 D02 R590, Ireland.
33Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, 152-160 Pearse Street, Dublin 2 D02 R590, Ireland.
34Department of Computer Science, University College London, London WC1E 6BT, U.K.
35Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
36Stony Brook University, Department of Applied Mathematics & Statistics, Stony Brook, New York 11794-3600, United States.
37Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, 08826 Seoul, South Korea.
38College of Pharmacy, Seoul National University, 08826 Seoul, South Korea.
39Arontier Co., 06784 Seoul, South Korea.
40Boehringer Ingelheim Pharma GmbH & Co., KG, Birkendorfer Str. 65, 88397 Biberach an der Riss, Germany.
41Institute for Drug Discovery, Faculty of Medicine, Faculty of Mathematics and Informatics, Faculty of Chemistry and Mineralogy, University Leipzig, Leipzig 04109, Germany.
42Center for Scalable Data Analytics and Artificial Intelligence ScaDS.AI Dresden/Leipzig and School of Embedded Composite Artificial Intelligence SECAI, Dresden/Leipzig 01062, Germany.
43Department of Chemistry, Department of Pharmacology, Center for Structural Biology, Institute of Chemical Biology, Center for Applied Artificial Intelligence in Protein Dynamics, Vanderbilt University, Nashville, Tennessee 37240-0002, United States.
44Department of Chemistry, Center for Structural Biology, Vanderbilt University, South Nashville, Nashville, Tennessee 37240-0002, United States.
45Chemspace, Kyiv 02094, Ukraine.
46Center for Natural Product Systems Biology, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea.
47Experts System Inc.,12730 High Bluff Drive, Suite 100, San Diego, California 92130, United States.
48AI Centre, Department of Computer Science, University College London, London WC1E 6BT, U.K.
49School of Pharmacy and Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-be-University, Indore, Madhya Pradesh 453112, India.
50Nuvisan ICB GmbH, Berlin 13353, Germany.
51Laboratoire d'Innovation Thérapeutique, UMR7200 CNRS-Université de Strasbourg, 67400 Illkirch, France.
52Department of Physics and Astronomy, University College London, London WC1E 6BT, U.K.
53UCB Pharma, Braine-L'Alleud 1420, Belgium.
54Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui 230000, China.
55Department of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, Aalborg, DK-9220, Denmark.
56Taras Shevchenko National University of Kyiv, Kyiv 01033, Ukraine.
57WE-SPARK Health Institute, 401 Sunset Avenue, Windsor, Ontario N9B 3P4, Canada.
58Conscience Medicines Network, Toronto, Ontario M5G 1L7, Canada.
59Relay Therapeutics, Cambridge, Massachusetts 02141, United States.
60Boehringer Ingelheim RCV, Dr. Boehringer-Gasse 5-11, 1121 Vienna, Austria.
61Boehringer Ingelheim Pharma GmbH & Co., KG, Birkendorfer Str. 65, Biberach an der Riss 88397, Germany.
62Shanghai Jiao Tong University, Shanghai 200030, China.
Abstract
The third Critical Assessment of Computational Hit-finding Experiments (CACHE) challenged computational teams to identify chemically novel ligands targeting the macrodomain 1 of SARS-CoV-2 Nsp3, a promising coronavirus drug target. Twenty-three groups deployed diverse design strategies to collectively select 1739 ligand candidates. While over 85% of the designed molecules were chemically novel, th…
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