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

Izhar Wallach, Denzil Bernard, Kong Nguyen, Gregory Ho, Adrian Morrison, Adrian Stecula, Andreana Rosnik, Ann Marie O’Sullivan, Aram Davtyan, Ben Samudio, Bill Thomas, Brad Worley, Brittany Butler, Christian Laggner, Desiree Thayer, Ehsan Moharreri, Greg Friedland, Ha Truong, Henry van den Bedem, Ho Leung NgKate Stafford, Krishna Sarangapani, Kyle Giesler, Lien Ngo, Michael Mysinger, Mostafa Ahmed, Nicholas J. Anthis, Niel Henriksen, Pawel Gniewek, Sam Eckert, Saulo de Oliveira, Shabbir Suterwala, Srimukh Veccham Krishna PrasadPrasad, Stefani Shek, Stephanie Contreras, Stephanie Hare, Teresa Palazzo, Terrence E. O’Brien, Tessa Van Grack, Tiffany Williams, Ting Rong Chern, Victor Kenyon, Andreia H. Lee, Andrew B. Cann, Bastiaan Bergman, Brandon M. Anderson, Bryan D. Cox, Jeffrey M. Warrington, Jon M. Sorenson, Joshua M. Goldenberg, Matthew A. Young, Nicholas DeHaan, Ryan P. Pemberton, Stefan Schroedl, Tigran M. Abramyan, Tushita Gupta, Venkatesh Mysore, Adam G. Presser, Adolfo A. Ferrando, Adriano D. Andricopulo, Agnidipta Ghosh, Aicha Gharbi Ayachi, Aisha Mushtaq, Ala M. Shaqra, Alan Kie Leong Toh, Alan V. Smrcka, Alberto Ciccia, Aldo Sena de Oliveira, Aleksandr Sverzhinsky, Alessandra Mara de Sousa, Alexander I. Agoulnik, Alexander Kushnir, Alexander N. Freiberg, Alexander V. Statsyuk, Alexandre R. Gingras, Alexei Degterev, Alexey Tomilov, Alice Vrielink, Alisa A. Garaeva, Amanda Bryant-Friedrich, Amedeo Caflisch, Amit K. Patel, Amith Vikram Rangarajan, An Matheeussen, Andrea Battistoni, Andrea Caporali, Andrea Chini, Andrea Ilari, Andrea Mattevi, Andrea Talbot Foote, Andrea Trabocchi, Andreas Stahl, Andrew B. Herr, Andrew Berti, Andrew Freywald, Andrew G. Reidenbach, Andrew Lam, Andrew R. Cuddihy, Andrew White, Angelo Taglialatela, Anil K. Ojha, Ann M. Cathcart, Anna A.L. Motyl, Anna Borowska, Anna D’Antuono, Anna K.H. Hirsch, Anna Maria Porcelli, Anna Minakova, Anna Montanaro, Anna Müller, Annarita Fiorillo, Anniina Virtanen, Anthony J. O’Donoghue, Antonio Del Rio Flores, Antonio E. Garmendia, Antonio Pineda-Lucena, Antonito T. Panganiban, Ariela Samantha, Arnab K. Chatterjee, Arthur L. Haas, Ashleigh S. Paparella, Ashley L.St John, Ashutosh Prince, Assmaa ElSheikh, Athena Marie Apfel, Audrey Colomba, Austin O’Dea, Bakary N’tji Diallo, Beatriz Murta Rezende Moraes Ribeiro, Ben A. Bailey-Elkin, Benjamin L. Edelman, Benjamin Liou, Benjamin Perry, Benjamin Soon Kai Chua, Benjámin Kováts, Bernhard Englinger, Bijina Balakrishnan, Bin Gong, Bogos Agianian, Brandon Pressly, Brenda P.Medellin Salas, Brendan M. Duggan, Brian V. Geisbrecht, Brian W. Dymock, Brianna C. Morten, Bruce D. Hammock, Bruno Eduardo Fernandes Mota, Bryan C. Dickinson, Cameron Fraser, Camille Lempicki, Carl D. Novina, Carles Torner, Carlo Ballatore, Carlotta Bon, Carly J. Chapman, Carrie L. Partch, Catherine T. Chaton, Chang Huang, Chao Yie Yang, Charlene M. Kahler, Charles Karan, Charles Keller, Chelsea L. Dieck, Chen Huimei, Chen Liu, Cheryl Peltier, Chinmay Kumar Mantri, Chinyere Maat Kemet, Christa E. Müller, Christian Weber, Christina M. Zeina, Christine S. Muli, Christophe Morisseau, Cigdem Alkan, Clara Reglero, Cody A. Loy, Cornelia M. Wilson, Courtney Myhr, Cristina Arrigoni, Cristina Paulino, César Santiago, Dahai Luo, Damon J. Tumes, Daniel A. Keedy, Daniel A. Lawrence, Daniel Chen, Danny Manor, Darci J. Trader, David A. Hildeman, David H. Drewry, David J. Dowling, David J. Hosfield, David M. Smith, David Moreira, David P. Siderovski, David Shum, David T. Krist, David W.H. Riches, Davide Maria Ferraris, Deborah H. Anderson, Deirdre R. Coombe, Derek S. Welsbie, Di Hu, Diana Ortiz, Dina Alramadhani, Dingqiang Zhang, Dipayan Chaudhuri, Dirk J. Slotboom, Donald R. Ronning, Donghan Lee, Dorian Dirksen, Douglas A. Shoue, Douglas William Zochodne, Durga Krishnamurthy, Dustin Duncan, Dylan M. Glubb, Edoardo Luigi Maria Gelardi, Edward C. Hsiao, Edward G. Lynn, Elany Barbosa Silva, Elena Aguilera, Elena Lenci, Elena Theres Abraham, Eleonora Lama, Eleonora Mameli, Elisa Leung, Emily M. Christensen, Emily R. Mason, Enrico Petretto, Ephraim F. Trakhtenberg, Eric J. Rubin, Erick Strauss, Erik W. Thompson, Erika Cione, Erika Mathes Lisabeth, Erkang Fan, Erna Geessien Kroon, Eunji Jo, Eva M. García-Cuesta, Evgenia Glukhov, Evripidis Gavathiotis, Fang Yu, Fei Xiang, Fenfei Leng, Feng Wang, Filippo Ingoglia, Focco van den Akker, Francesco Borriello, Franco J. Vizeacoumar, Frank Luh, Frederick S. Buckner, Frederick S. Vizeacoumar, Fredj Ben Bdira, Fredrik Svensson, G. Marcela Rodriguez, Gabriella Bognár, Gaia Lembo, Gang Zhang, Garrett Dempsey, Gary Eitzen, Gaétan Mayer, Geoffrey L. Greene, George A. Garcia, Gergely L. Lukacs, Gergely Prikler, Gian Carlo G. Parico, Gianni Colotti, Gilles De Keulenaer, Gino Cortopassi, Giovanni Roti, Giulia Girolimetti, Giuseppe Fiermonte, Giuseppe Gasparre, Giuseppe Leuzzi, Gopal Dahal, Gracjan Michlewski, Graeme L. Conn, Grant David Stuchbury, Gregory R. Bowman, Grzegorz Maria Popowicz, Guido Veit, Guilherme Eduardo de Souza, Gustav Akk, Guy Caljon, Guzmán Alvarez, Gwennan Rucinski, Gyeongeun Lee, Gökhan Cildir, Hai Li, Hairol E. Breton, Hamed Jafar-Nejad, Han Zhou, Hannah P. Moore, Hannah Tilford, Haynes Yuan, Heesung Shim, Heike Wulff, Heinrich Hoppe, Helena Chaytow, Heng Keat Tam, Holly Van Remmen, Hongyang Xu, Hosana Maria Debonsi, Howard B. Lieberman, Hoyoung Jung, Hua Ying Fan, Hui Feng, Hui Zhou, Hyeong Jun Kim, Iain R. Greig, Ileana Caliandro, Ileana Corvo, Imanol Arozarena, Imran N. Mungrue, Ingrid M. Verhamme, Insaf Ahmed Qureshi, Irina Lotsaris, Isin Cakir, J. Jefferson P. Perry, Jacek Kwiatkowski, Jacob Boorman, Jacob Ferreira, Jacob Fries, Jadel Müller Kratz, Jaden Miner, Jair L. Siqueira-Neto, James G. Granneman, James Ng, James Shorter, Jan Hendrik Voss, Jan M. Gebauer, Janelle Chuah, Jarrod J. Mousa, Jason T. Maynes, Jay D. Evans, Jeffrey Dickhout, Jeffrey P. MacKeigan, Jennifer N. Jossart, Jia Zhou, Jiabei Lin, Jiake Xu, Jianghai Wang, Jiaqi Zhu, Jiayu Liao, Jingyi Xu, Jinshi Zhao, Jiusheng Lin, Jiyoun Lee, Joana Reis, Joerg Stetefeld, John B. Bruning, John Burt Bruning, John G. Coles, John J. Tanner, John M. Pascal, Jonathan So, Jordan L. Pederick, Jose A. Costoya, Joseph B. Rayman, Joseph J. Maciag, Joshua Alexander Nasburg, Joshua J. Gruber, Joshua M. Finkelstein, Joshua Watkins, José Miguel Rodríguez-Frade, Juan Antonio Sanchez Arias, Juan José Lasarte, Julen Oyarzabal, Julian Milosavljevic, Julie Cools, Julien Lescar, Julijus Bogomolovas, Jun Wang, Jung Min Kee, Jung Min Kee, Junzhuo Liao, Jyothi C. Sistla, Jônatas Santos Abrahão, Kamakshi Sishtla, Karol R. Francisco, Kasper B. Hansen, Kathleen A. Molyneaux, Kathryn A. Cunningham, Katie R. Martin, Kavita Gadar, Kayode K. Ojo, Keith S. Wong, Kelly L. Wentworth, Kent Lai, Kevin A. Lobb, Kevin M. Hopkins, Keykavous Parang, Khaled Machaca, Kien Pham, Kim Ghilarducci, Kim S. Sugamori, Kirk James McManus, Kirsikka Musta, Kiterie M.E. Faller, Kiyo Nagamori, Konrad J. Mostert, Konstantin V. Korotkov, Koting Liu, Kristiana S. Smith, Kristopher Sarosiek, Kyle H. Rohde, Kyu Kwang Kim, Kyung Hyeon Lee, Lajos Pusztai, Lari Lehtiö, Larisa M. Haupt, Leah E. Cowen, Lee J. Byrne, Leila Su, Leon Wert-Lamas, Leonor Puchades-Carrasco, Lifeng Chen, Linda H. Malkas, Ling Zhuo, Lizbeth Hedstrom, Lizbeth Hedstrom, Loren D. Walensky, Lorenzo Antonelli, Luisa Iommarini, Luke Whitesell, Lía M. Randall, M. Dahmani Fathallah, Maira Harume Nagai, Mairi Louise Kilkenny, Manu Ben-Johny, Marc P. Lussier, Marc P. Windisch, Marco Lolicato, Marco Lucio Lolli, Margot Vleminckx, Maria Cristina Caroleo, Maria J. Macias, Marilia Valli, Marim M. Barghash, Mario Mellado, Mark A. Tye, Mark A. Wilson, Mark Hannink, Mark R. Ashton, Mark Vincent C.dela Cerna, Marta Giorgis, Martin K. Safo, Martin St Maurice, Mary Ann McDowell, Marzia Pasquali, Masfique Mehedi, Mateus Sá Magalhães Serafim, Matthew B. Soellner, Matthew G. Alteen, Matthew M. Champion, Maxim Skorodinsky, Megan L. O’Mara, Mel Bedi, Menico Rizzi, Michael Levin, Michael Mowat, Michael R. Jackson, Mikell Paige, Minnatallah Al-Yozbaki, Miriam A. Giardini, Mirko M. Maksimainen, Monica De Luise, Muhammad Saddam Hussain, Myron Christodoulides, Natalia Stec, Natalia Zelinskaya, Natascha Van Pelt, Nathan M. Merrill, Nathanael Singh, Neeltje A. Kootstra, Neeraj Singh, Neha S. Gandhi, Nei Li Chan, Nguyen Mai Trinh, Nicholas O. Schneider, Nick Matovic, Nicola Horstmann, Nicola Longo, Nikhil Bharambe, Nirvan Rouzbeh, Niusha Mahmoodi, Njabulo Joyfull Gumede, Noelle C. Anastasio, Noureddine Ben Khalaf, Obdulia Rabal, Olga Kandror, Olivier Escaffre, Olli Silvennoinen, Ozlem Tastan Bishop, Pablo Iglesias, Pablo Sobrado, Patrick Chuong, Patrick O’Connell, Pau Martin-Malpartida, Paul Mellor, Paul V. Fish, Paulo Otávio Lourenço Moreira, Pei Zhou, Pengda Liu, Pengda Liu, Pengpeng Wu, Percy Agogo-Mawuli, Peter L. Jones, Peter Ngoi, Peter Toogood, Philbert Ip, Philipp von Hundelshausen, Pil H. Lee, Rachael B. Rowswell-Turner, Rafael Balaña-Fouce, Rafael Eduardo Oliveira Rocha, Rafael V.C. Guido, Rafaela Salgado Ferreira, Rajendra K. Agrawal, Rajesh K. Harijan, Rajesh Ramachandran, Rajkumar Verma, Rakesh K. Singh, Rakesh Kumar Tiwari, Ralph Mazitschek, Rama K. Koppisetti, Remus T. Dame, Renée N. Douville, Richard C. Austin, Richard E. Taylor, Richard G. Moore, Richard H. Ebright, Richard M. Angell, Riqiang Yan, Rishabh Kejriwal, Robert A. Batey, Robert Blelloch, Robert J. Vandenberg, Robert J. Hickey, Robert J. Kelm, Robert J. Lake, Robert K. Bradley, Robert M. Blumenthal, Roberto Solano, Robin Matthias Gierse, Ronald E. Viola, Ronan R. McCarthy, Rosa Maria Reguera, Ruben Vazquez Uribe, Rubens Lima do Monte-Neto, Ruggiero Gorgoglione, Ryan T. Cullinane, Sachin Katyal, Sakib Hossain, Sameer Phadke, Samuel A. Shelburne, Sandra E. Geden, Sandra Johannsen, Sarah Wazir, Scott Legare, Scott M. Landfear, Senthil K. Radhakrishnan, Serena Ammendola, Sergei Dzhumaev, Seung Yong Seo, Shan Li, Shan Zhou, Shaoyou Chu, Shefali Chauhan, Shinsaku Maruta, Shireen R. Ashkar, Show Ling Shyng, Silvestro G. Conticello, Silvia Buroni, Silvia Garavaglia, Simon J. White, Siran Zhu, Sofiya Tsimbalyuk, Somaia Haque Chadni, Soo Young Byun, Soonju Park, Sophia Q. Xu, Sourav Banerjee, Stefan Zahler, Stefano Espinoza, Stefano Gustincich, Stefano Sainas, Stephanie L. Celano, Stephen J. Capuzzi, Stephen N. Waggoner, Steve Poirier, Steven H. Olson, Steven O. Marx, Steven R. Van Doren, Suryakala Sarilla, Susann M. Brady-Kalnay, Sydney Dallman, Syeda Maryam Azeem, Tadahisa Teramoto, Tamar Mehlman, Tarryn Swart, Tatjana Abaffy, Tatos Akopian, Teemu Haikarainen, Teresa Lozano Moreda, Tetsuro Ikegami, Thaiz Rodrigues Teixeira, Thilina D. Jayasinghe, Thomas H. Gillingwater, Thomas Kampourakis, Timothy I. Richardson, Timothy J. Herdendorf, Timothy J. Kotzé, Timothy R. O’Meara, Timothy W. Corson, Tobias Hermle, Tomisin Happy Ogunwa, Tong Lan, Tong Su, Toshihiro Banjo, Tracy A. O’Mara, Tristan Chou, Tsui Fen Chou, Ulrich Baumann, Umesh R. Desai, Vaibhav P. Pai, Van Chi Thai, Vasudha Tandon, Versha Banerji, Victoria L. Robinson, Vignesh Gunasekharan, Vigneshwaran Namasivayam, Vincent F.M. Segers, Vincent Maranda, Vincenza Dolce, Vinícius Gonçalves Maltarollo, Viola Camilla Scoffone, Virgil A. Woods, Virginia Paola Ronchi, Vuong Van Hung Le, W. Brent Clayton, W. Todd Lowther, Walid A. Houry, Wei Li, Weiping Tang, Wenjun Zhang, Wesley C. Van Voorhis, William A. Donaldson, William C. Hahn, William G. Kerr, William H. Gerwick, William J. Bradshaw, Wuen Ee Foong, Xavier Blanchet, Xiaoyang Wu, Xin Lu, Xin Qi, Xin Xu, Xinfang Yu, Xingping Qin, Xingyou Wang, Xinrui Yuan, Xu Zhang, Yan Jessie Zhang, Yanmei Hu, Yasser Ali Aldhamen, Yicheng Chen, Yihe Li, Ying Sun, Yini Zhu, Yogesh K. Gupta, Yolanda Pérez-Pertejo, Yong Li, Young Tang, Yuan He, Yuk Ching Tse-Dinh, Yulia A. Sidorova, Yun Yen, Yunlong Li, Zachary J. Frangos, Zara Chung, Zhengchen Su, Zhenghe Wang, Zhiguo Zhang, Zhongle Liu, Zintis Inde, Zoraima Artía, Abraham Heifets

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number7526
Pages (from-to)7526
JournalScientific Reports
Volume14
Issue number1
DOIs
StatePublished - Apr 2 2024

Keywords

  • High-Throughput Screening Assays/methods
  • Drug Discovery/methods
  • Small Molecule Libraries/pharmacology

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