CACHE Challenge #2: Targeting the RNA Site of the SARS-CoV-2 Helicase Nsp13.

Journal: Journal of chemical information and modeling
Published Date:

Abstract

A critical assessment of computational hit-finding experiments (CACHE) challenge was conducted to predict ligands for the SARS-CoV-2 Nsp13 helicase RNA binding site, a highly conserved COVID-19 target. Twenty-three participating teams comprised of computational chemists and data scientists used protein structure and data from fragment-screening paired with advanced computational and machine learning methods to each predict up to 100 inhibitory ligands. Across all teams, 1957 compounds were predicted and were subsequently procured from commercial catalogs for biophysical assays. Of these compounds, 0.7% were confirmed to bind to Nsp13 in a surface plasmon resonance assay. The six best-performing computational workflows used fragment growing, active learning, or conventional virtual screening with and without complementary deep-learning scoring functions. Follow-up functional assays resulted in identification of two compound scaffolds that bound Nsp13 with a below 10 μM and inhibited helicase activity. Overall, CACHE #2 participants were successful in identifying hit compound scaffolds targeting Nsp13, a central component of the coronavirus replication-transcription complex. Computational design strategies recurrently successful across the first two CACHE challenges include linking or growing docked or crystallized fragments and docking small and diverse libraries to train ultrafast machine-learning models. The CACHE #2 competition reveals how crowd-sourcing ligand prediction efforts using a distinct array of approaches followed with critical biophysical assays can result in novel lead compounds to advance drug discovery efforts.

Authors

  • Oleksandra Herasymenko
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Madhushika Silva
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Abd Al-Aziz A Abu-Saleh
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Ayaz Ahmad
    Department of Civil Engineering, COMSATS University Islamabad, Abbottabadm, 22060, Pakistan. Electronic address: ayazahmad@cuiatd.edu.pk.
  • Jesus Alvarado-Huayhuaz
    Center for Computational Sciences, Universidade Federal do Rio Grande - FURG, Rio Grande 96201-900, Brazil.
  • Oscar E A Arce
    Center for Computational Sciences, Universidade Federal do Rio Grande - FURG, Rio Grande 96201-900, Brazil.
  • Roly J Armstrong
    School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, United Kingdom.
  • Cheryl Arrowsmith
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Kelly E Bachta
    Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • Hartmut Beck
    Bayer AG, Drug Discovery Sciences, Wuppertal, 42096, Germany.
  • Dénes Berta
    Department of Physics and Astronomy, University College London, London WC1E 6BT, United Kingdom.
  • Mateusz K Bieniek
    School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, United Kingdom.
  • Vincent Blay
    Fisher College of Business , The Ohio State University , Gerlach Hall, 2108 Neil Avenue, Columbus , Ohio 43210 , United States.
  • Albina Bolotokova
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Philip E Bourne
    University of Virginia, Data Science Institute, Charlottesville, VA, USA; University of Virginia, Department of Biomedical Engineering, Charlottesville, VA, USA.
  • Marko Breznik
    Computational Molecular Design, Institute of Pharmacy, Freie Universität Berlin, Königin-Luisestr. 2 + 4, Berlin 14195, Germany.
  • Peter J Brown
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Aaron D G Campbell
    School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, United Kingdom.
  • Emanuele Carosati
    Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
  • Irene Chau
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Daniel J Cole
    Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
  • Ben Cree
    School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, United Kingdom.
  • Wim Dehaen
    Molecular Design and Synthesis, Department of Chemistry, University of Leuven (KU Leuven), Campus Arenberg, P.O. Box 2404, Celestijnenlaan 200 F, 3001 Leuven, Belgium.
  • Katrin Denzinger
    Computational Molecular Design, Institute of Pharmacy, Freie Universität Berlin, Königin-Luisestr. 2 + 4, Berlin 14195, Germany.
  • Karina Dos Santos Machado
    Center for Computational Sciences, Universidade Federal do Rio Grande - FURG, Rio Grande 96201-900, Brazil.
  • Ian Dunn
    Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
  • Prasannavenkatesh Durai
    Natural Product Informatics Research Center, KIST Gangneung Institute of Natural Products, Gangneung 25451, Republic of Korea.
  • Kristina Edfeldt
    Structural Genomics Consortium, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
  • Aled Edwards
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Darren Fayne
    DCU Life Sciences Institute, Dublin City University, Dublin, D09 DXA0, Ireland.
  • Daniel Felfoldi
    Department of Physics and Astronomy, University College London, London WC1E 6BS, United Kingdom.
  • Kallie Friston
    School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, United Kingdom.
  • Pegah Ghiabi
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Elisa Gibson
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Judith Günther
    Bayer AG Research and Development, Computational Molecular Design, Berlin, Germany.
  • Anders Gunnarsson
    Structure and Biophysics, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, Mölndal, Gothenburg 431 50, Sweden.
  • Alexander Hillisch
    Bayer AG , Drug Discovery, Chemical Research , 42096 Wuppertal , Germany.
  • Douglas R Houston
    Institute of Quantitative Biology, Biochemistry and Biotechnology, University of Edinburgh, Edinburgh, Scotland EH9 3BF, UK. Electronic address: DouglasR.Houston@ed.ac.uk.
  • Jan Halborg Jensen
    Department of Chemistry, University of Copenhagen, Universitetsparken 5, Copenhagen 2100, Denmark.
  • Rachel J Harding
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Kate S Harris
    School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, United Kingdom.
  • Laurent Hoffer
    Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
  • Anders Hogner
    Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 431 50, Sweden.
  • Joshua T Horton
    School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, U.K.
  • Scott Houliston
    Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada.
  • Judd F Hultquist
    Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • Ashley Hutchinson
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • John J Irwin
    Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.
  • Marko Jukič
    Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
  • Shubhangi Kandwal
    Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2 D02 R590, Ireland.
  • Andrea Karlova
    Department of Computer Science, University College London, London OX3 7DQ, United Kingdom.
  • Vittorio L Katis
    Centre for Medicines Discovery, NDM Research Building, University of Oxford, Oxford OX3 7FZ, U.K.
  • Ryan P Kich
    Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • Dmitri Kireev
    Department of Chemistry, University of Missouri, Columbia, Missouri 65211-7600, United States of America.
  • David Koes
    Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
  • Nicole L Inniss
    Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 United States of America.
  • Uta Lessel
    Boehringer Ingelheim Pharma GmbH & Co. KG Birkendorfer Str. 65, Biberach an der Riss 88397, Germany.
  • Sijie Liu
    Computational Molecular Design, Institute of Pharmacy, Freie Universität Berlin, Königin-Luisestr. 2 + 4, Berlin 14195, Germany.
  • Peter Loppnau
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Wei Lu
    Department of Pharmacy, Taihe Hospital, Hubei University of Medicine, Shiyan, China.
  • Sam Martino
    Department of Physics and Astronomy, University College London, London WC1E 6BS, United Kingdom.
  • Miles McGibbon
    Institute of Quantitative Biology, Biochemistry and Biotechnology, University of Edinburgh, Edinburgh, Scotland EH9 3BF, UK.
  • Jens Meiler
    Department of Chemistry, Vanderbilt University, Nashville, TN, United States.
  • Akhila Mettu
    Department of Chemistry, University of Missouri, Columbia, Missouri 65211-7600, United States of America.
  • Sam Money-Kyrle
    Institute of Quantitative Biology, Biochemistry and Biotechnology, University of Edinburgh, Edinburgh, Scotland EH9 3BF, UK.
  • Rocco Moretti
    Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
  • Yurii S Moroz
    Taras Shevchenko National University of Kyiv, Kyiv, Ukraine.
  • Charuvaka Muvva
    BiomAILS India Pvt Ltd., Hyderabad 500 090, India.
  • Joseph A Newman
    Centre for Medicines Discovery, NDM Research Building, University of Oxford, Oxford OX3 7FZ, U.K.
  • Leon Obendorf
    Institute for Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
  • Brooks Paige
    Centre for Artificial Intelligence, University College London, WC1E 6BT, United Kingdom.
  • Amit Pandit
    Computational Molecular Design, Institute of Pharmacy, Freie Universität Berlin, Königin-Luisestr. 2 + 4, Berlin 14195, Germany.
  • Keunwan Park
    Natural Product Informatics Research Center, KIST Gangneung Institute of Natural Products, Gangneung 25451, Republic of Korea.
  • Sumera Perveen
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Rachael Pirie
    School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, United Kingdom.
  • Gennady Poda
    Drug Discovery Program, Ontario Institute for Cancer Research, MaRS Centre, 661 University Avenue, Suite 510, Toronto, Ontario, M5G 0A3, Canada.
  • Mykola Protopopov
    Chemspace, Kyiv 02094, Ukraine.
  • Vera Pütter
    Nuvisan ICB GmBH, Berlin 13353, Germany.
  • Federico Ricci
    University of Messina, Messina 98122, Italy.
  • Natalie J Roper
    School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne NE1 7RU, United Kingdom.
  • Edina Rosta
    Department of Chemistry, King's College London, London SE1 1DB, United Kingdom.
  • Margarita Rzhetskaya
    Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
  • Yogesh Sabnis
    UCB, Braine-L'Alleud 1420, Belgium.
  • Karla J F Satchell
    Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 United States of America.
  • Frederico Schmitt Kremer
    OmixLab, Universidade Federal de Pelotas, Capão do Leão 96010-610, Brazil.
  • Thomas Scott
    Center for Structural Biology, Vanderbilt University, South Nashville, Nashville, Tennessee 37240-0002, United States of America.
  • Almagul Seitova
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
  • Casper Steinmann
    Department of Chemistry and Bioscience, Aalborg University, Fredrik Bajers Vej 7H, Aalborg 9220, Denmark.
  • Valerij Talagayev
    Computational Molecular Design, Institute of Pharmacy, Freie Universität Berlin, Königin-Luisestr. 2 + 4, Berlin 14195, Germany.
  • Olga O Tarkhanova
    Chemspace LLC, Kyiv 02094, Ukraine.
  • Natalie J Tatum
    Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne NE2 4HH, U.K.
  • Dakota Treleaven
    Conscience Medicines Network, Toronto, Ontario M5G 1L7 Canada.
  • Adriano Velasque Werhli
    Center for Computational Sciences, Universidade Federal do Rio Grande - FURG, Rio Grande 96201-900, Brazil.
  • W Patrick Walters
    Relay Therapeutics, Cambridge, MA, USA.
  • Xiaowen Wang
    Bioresources Green Transformation Collaborative Innovation Center of Hubei Province, College of Life Sciences, Hubei University, Wuhan 430062, Hubei, China.
  • Jude Wells
    Centre for Artificial Intelligence, University College London, WC1E 6BT, United Kingdom.
  • Geoffrey Wells
    Department of Pharmaceutical and Biological Chemistry, University College London, London WC1E 6BT, United Kingdom.
  • Yvonne Westermaier
    Boehringer Ingelheim RCV, Dr. Boehringer-Gasse 5-11, Vienna 1121, Austria.
  • Gerhard Wolber
    Computational Molecular Design, Institute of Pharmacy, Freie Universität Berlin, Königin-Luisestr. 2 + 4, Berlin 14195, Germany.
  • Lars Wortmann
    Boehringer Ingelheim Pharma GmbH & Co. KG Birkendorfer Str. 65, Biberach an der Riss 88397, Germany.
  • Jixian Zhang
    Aladdin Healthcare Technologies Ltd.
  • Zheng Zhao
    College of Bioinformatics Science and Technology and Bio-Pharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Nangang, Harbin, Heilongjiang, China.
  • Shuangjia Zheng
    Research Center for Drug Discovery, School of Pharmaceutical Sciences , Sun Yat-sen University , 132 East Circle at University City , Guangzhou 510006 , China.
  • Matthieu Schapira
    Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.