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Published April 2, 2024 | Version Published
Journal Article Open

AI is a viable alternative to high throughput screening: a 318-target study

Creators

  • Wallach, Izhar ORCID icon
  • Bernard, Denzil
  • Nguyen, Kong
  • Ho, Gregory
  • Morrison, Adrian
  • Stecula, Adrian
  • Rosnik, Andreana
  • O'Sullivan, Ann Marie
  • Davtyan, Aram
  • Samudio, Ben
  • Thomas, Bill
  • Worley, Brad
  • Butler, Brittany
  • Laggner, Christian
  • Thayer, Desiree
  • Moharreri, Ehsan
  • Friedland, Greg
  • Truong, Ha
  • van den Bedem, Henry
  • Ng, Ho Leung
  • Stafford, Kate
  • Sarangapani, Krishna
  • Giesler, Kyle
  • Ngo, Lien
  • Mysinger, Michael
  • Ahmed, Mostafa
  • Anthis, Nicholas J.
  • Henriksen, Niel
  • Gniewek, Pawel
  • Eckert, Sam
  • de Oliveira, Saulo
  • Suterwala, Shabbir
  • PrasadPrasad, Srimukh Veccham Krishna
  • Shek, Stefani
  • Contreras, Stephanie
  • Hare, Stephanie
  • Palazzo, Teresa
  • O'Brien, Terrence E.
  • Van Grack, Tessa
  • Williams, Tiffany
  • Chern, Ting-Rong
  • Kenyon, Victor
  • Lee, Andreia H.
  • Cann, Andrew B.
  • Bergman, Bastiaan
  • Anderson, Brandon M.
  • Cox, Bryan D.
  • Warrington, Jeffrey M.
  • Sorenson, Jon M.
  • Goldenberg, Joshua M.
  • Young, Matthew A.
  • DeHaan, Nicholas
  • Pemberton, Ryan P.
  • Schroedl, Stefan
  • Abramyan, Tigran M.
  • Gupta, Tushita
  • Mysore, Venkatesh
  • Presser, Adam G.
  • Ferrando, Adolfo A.
  • Andricopulo, Adriano D.
  • Ghosh, Agnidipta
  • Ayachi, Aicha Gharbi
  • Mushtaq, Aisha
  • Shaqra, Ala M.
  • Toh, Alan Kie Leong
  • Smrcka, Alan V.
  • Ciccia, Alberto
  • de Oliveira, Aldo Sena
  • Sverzhinsky, Aleksandr
  • de Sousa, Alessandra Mara
  • Agoulnik, Alexander I.
  • Kushnir, Alexander
  • Freiberg, Alexander N.
  • Statsyuk, Alexander V.
  • Gingras, Alexandre R.
  • Degterev, Alexei
  • Tomilov, Alexey
  • Vrielink, Alice
  • Garaeva, Alisa A.
  • Bryant-Friedrich, Amanda
  • Caflisch, Amedeo
  • Patel, Amit K.
  • Rangarajan, Amith Vikram
  • Matheeussen, An
  • Battistoni, Andrea
  • Caporali, Andrea
  • Chini, Andrea
  • Ilari, Andrea
  • Mattevi, Andrea
  • Foote, Andrea Talbot
  • Trabocchi, Andrea
  • Stahl, Andreas
  • Herr, Andrew B.
  • Berti, Andrew
  • Freywald, Andrew
  • Reidenbach, Andrew G.
  • Lam, Andrew
  • Cuddihy, Andrew R.
  • White, Andrew
  • Taglialatela, Angelo
  • Ojha, Anil K.
  • Cathcart, Ann M.
  • Motyl, Anna A. L.
  • Borowska, Anna
  • D'Antuono, Anna
  • Hirsch, Anna K. H.
  • Porcelli, Anna Maria
  • Minakova, Anna
  • Montanaro, Anna
  • Müller, Anna
  • Fiorillo, Annarita
  • Virtanen, Anniina
  • O'Donoghue, Anthony J.
  • Del Rio Flores, Antonio
  • Garmendia, Antonio E.
  • Pineda-Lucena, Antonio
  • Panganiban, Antonito T.
  • Samantha, Ariela
  • Chatterjee, Arnab K.
  • Haas, Arthur L.
  • Paparella, Ashleigh S.
  • John, Ashley L. St.
  • Prince, Ashutosh
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  • Colomba, Audrey
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  • Bailey-Elkin, Ben A.
  • Edelman, Benjamin L.
  • Liou, Benjamin
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  • Chua, Benjamin Soon Kai
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  • Agianian, Bogos
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  • Keller, Charles
  • Dieck, Chelsea L.
  • Huimei, Chen
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  • Peltier, Cheryl
  • Mantri, Chinmay Kumar
  • Kemet, Chinyere Maat
  • Müller, Christa E.
  • Weber, Christian
  • Zeina, Christina M.
  • Muli, Christine S.
  • Morisseau, Christophe
  • Alkan, Cigdem
  • Reglero, Clara
  • Loy, Cody A.
  • Wilson, Cornelia M.
  • Myhr, Courtney
  • Arrigoni, Cristina
  • Paulino, Cristina
  • Santiago, César
  • Luo, Dahai
  • Tumes, Damon J.
  • Keedy, Daniel A.
  • Lawrence, Daniel A.
  • Chen, Daniel
  • Manor, Danny
  • Trader, Darci J.
  • Hildeman, David A.
  • Drewry, David H.
  • Dowling, David J.
  • Hosfield, David J.
  • Smith, David M.
  • Moreira, David
  • Siderovski, David P.
  • Shum, David
  • Krist, David T.
  • Riches, David W. H.
  • Ferraris, Davide Maria
  • Anderson, Deborah H.
  • Coombe, Deirdre R.
  • Welsbie, Derek S.
  • Hu, Di
  • Ortiz, Diana
  • Alramadhani, Dina
  • Zhang, Dingqiang
  • Chaudhuri, Dipayan
  • Slotboom, Dirk J.
  • Ronning, Donald R.
  • Lee, Donghan
  • Dirksen, Dorian
  • Shoue, Douglas A.
  • Zochodne, Douglas William
  • Krishnamurthy, Durga
  • Duncan, Dustin
  • Glubb, Dylan M.
  • Gelardi, Edoardo Luigi Maria
  • Hsiao, Edward C.
  • Lynn, Edward G.
  • Silva, Elany Barbosa
  • Aguilera, Elena
  • Lenci, Elena
  • Abraham, Elena Theres
  • Lama, Eleonora
  • Mameli, Eleonora
  • Leung, Elisa
  • Christensen, Emily M.
  • Mason, Emily R.
  • Petretto, Enrico
  • Trakhtenberg, Ephraim F.
  • Rubin, Eric J.
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  • Thompson, Erik W.
  • Cione, Erika
  • Lisabeth, Erika Mathes
  • Fan, Erkang
  • Kroon, Erna Geessien
  • Jo, Eunji
  • García-Cuesta, Eva M.
  • Glukhov, Evgenia
  • Gavathiotis, Evripidis
  • Yu, Fang
  • Xiang, Fei
  • Leng, Fenfei
  • Wang, Feng ORCID icon
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  • van den Akker, Focco
  • Borriello, Francesco
  • Vizeacoumar, Franco J.
  • Luh, Frank
  • Buckner, Frederick S.
  • Vizeacoumar, Frederick S.
  • Bdira, Fredj Ben
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  • Rodriguez, G. Marcela
  • Bognár, Gabriella
  • Lembo, Gaia
  • Zhang, Gang
  • Dempsey, Garrett
  • Eitzen, Gary
  • Mayer, Gaétan
  • Greene, Geoffrey L.
  • Garcia, George A.
  • Lukacs, Gergely L.
  • Prikler, Gergely
  • Parico, Gian Carlo G.
  • Colotti, Gianni
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  • Leuzzi, Giuseppe
  • Dahal, Gopal
  • Michlewski, Gracjan
  • Conn, Graeme L.
  • Stuchbury, Grant David
  • Bowman, Gregory R.
  • Popowicz, Grzegorz Maria
  • Veit, Guido
  • de Souza, Guilherme Eduardo
  • Akk, Gustav
  • Caljon, Guy
  • Alvarez, Guzmán
  • Rucinski, Gwennan
  • Lee, Gyeongeun
  • Cildir, Gökhan
  • Li, Hai
  • Breton, Hairol E.
  • Jafar-Nejad, Hamed
  • Zhou, Han
  • Moore, Hannah P.
  • Tilford, Hannah
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  • Li, Yong
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  • Tse-Dinh, Yuk-Ching
  • Sidorova, Yulia A.
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  • Li, Yunlong
  • Frangos, Zachary J.
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  • Artía, Zoraima
  • Heifets, Abraham
  • Atomwise AIMS Program
  • 1. ROR icon California Institute of Technology

Abstract

High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery.

Acknowledgement

See Supplementary section S1.

 

Data Availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Copyright and License

© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Conflict of Interest

The authors affiliated with Atomwise declare the existence of a financial competing interest.

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https://doi.org/10.1038/s41598-024-54655-z
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Journal Article
Publisher
Nature Publishing Group
Published in
Scientific Reports, 14, 7526, ISSN: 2045-2322, 2024.
Languages
English

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Created
April 8, 2024
Modified
April 8, 2024
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