AI is a viable alternative to high throughput screening: a 318-target study
Authors:   The Atomwise AIMS Program, Wallach Izhar , 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 , ElSheikh Assmaa , Apfel Athena Marie , Colomba Audrey , O’Dea Austin , Diallo Bakary N’tji , Ribeiro Beatriz Murta Rezende Moraes , Bailey-Elkin Ben A. , Edelman Benjamin L. , Liou Benjamin , Perry Benjamin , Chua Benjamin Soon Kai , Kováts Benjámin , Englinger Bernhard , Balakrishnan Bijina , Gong Bin , Agianian Bogos , Pressly Brandon , Salas Brenda P. Medellin , Duggan Brendan M. , Geisbrecht Brian V. , Dymock Brian W. , Morten Brianna C. , Hammock Bruce D. , Mota Bruno Eduardo Fernandes , Dickinson Bryan C. , Fraser Cameron , Lempicki Camille , Novina Carl D. , Torner Carles , Ballatore Carlo , Bon Carlotta , Chapman Carly J. , Partch Carrie L. , Chaton Catherine T. , Huang Chang , Yang Chao-Yie , Kahler Charlene M. , Karan Charles , Keller Charles , Dieck Chelsea L. , Huimei Chen , Liu Chen , 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 , Giles Ellie , Christensen Emily M. , Mason Emily R. , Petretto Enrico , Trakhtenberg Ephraim F. , Rubin Eric J. , Strauss Erick , 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 , Ingoglia Filippo , van den Akker Focco , Borriello Francesco , Vizeacoumar Franco J. , Luh Frank , Buckner Frederick S. , Vizeacoumar Frederick S. , Bdira Fredj Ben , Svensson Fredrik , 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 , De Keulenaer Gilles , Cortopassi Gino , Roti Giovanni , Girolimetti Giulia , Fiermonte Giuseppe , Gasparre Giuseppe , 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 , Yuan Haynes , Shim Heesung , Wulff Heike , Hoppe Heinrich , Chaytow Helena , Tam Heng-Keat , Van Remmen Holly , Xu Hongyang , Debonsi Hosana Maria , Lieberman Howard B. , Jung Hoyoung , Fan Hua-Ying , Feng Hui , Zhou Hui , Kim Hyeong Jun , Greig Iain R. , Caliandro Ileana , Corvo Ileana , Arozarena Imanol , Mungrue Imran N. , Verhamme Ingrid M. , Qureshi Insaf Ahmed , Lotsaris Irina , Cakir Isin , Perry J. Jefferson P. , Kwiatkowski Jacek , Boorman Jacob , Ferreira Jacob , Fries Jacob , Kratz Jadel Müller , Miner Jaden , Siqueira-Neto Jair L. , Granneman James G. , Ng James , Shorter James , Voss Jan Hendrik , Gebauer Jan M. , Chuah Janelle , Mousa Jarrod J. , Maynes Jason T. , Evans Jay D. , Dickhout Jeffrey , MacKeigan Jeffrey P. , Jossart Jennifer N. , Zhou Jia , Lin Jiabei , Xu Jiake , Wang Jianghai , Zhu Jiaqi , Liao Jiayu , Xu Jingyi , Zhao Jinshi , Lin Jiusheng , Lee Jiyoun , Reis Joana , Stetefeld Joerg , Bruning John B. , Bruning John Burt , Coles John G. , Tanner John J. , Pascal John M. , So Jonathan , Pederick Jordan L. , Costoya Jose A. , Rayman Joseph B. , Maciag Joseph J. , Nasburg Joshua Alexander , Gruber Joshua J. , Finkelstein Joshua M. , Watkins Joshua , Rodríguez-Frade José Miguel , Arias Juan Antonio Sanchez , Lasarte Juan José , Oyarzabal Julen , Milosavljevic Julian , Cools Julie , Lescar Julien , Bogomolovas Julijus , Wang Jun , Kee Jung-Min , Kee Jung-Min , Liao Junzhuo , Sistla Jyothi C. , Abrahão Jônatas Santos , Sishtla Kamakshi , Francisco Karol R. , Hansen Kasper B. , Molyneaux Kathleen A. , Cunningham Kathryn A. , Martin Katie R. , Gadar Kavita , Ojo Kayode K. , Wong Keith S. , Wentworth Kelly L. , Lai Kent , Lobb Kevin A. , Hopkins Kevin M. , Parang Keykavous , Machaca Khaled , Pham Kien , Ghilarducci Kim , Sugamori Kim S. , McManus Kirk James , Musta Kirsikka , Faller Kiterie M. E. , Nagamori Kiyo , Mostert Konrad J. , Korotkov Konstantin V. , Liu Koting , Smith Kristiana S. , Sarosiek Kristopher , Rohde Kyle H. , Kim Kyu Kwang , Lee Kyung Hyeon , Pusztai Lajos , Lehtiö Lari , Haupt Larisa M. , Cowen Leah E. , Byrne Lee J. , Su Leila , Wert-Lamas Leon , Puchades-Carrasco Leonor , Chen Lifeng , Malkas Linda H. , Zhuo Ling , Hedstrom Lizbeth , Hedstrom Lizbeth , Walensky Loren D. , Antonelli Lorenzo , Iommarini Luisa , Whitesell Luke , Randall Lía M. , Fathallah M. Dahmani , Nagai Maira Harume , Kilkenny Mairi Louise , Ben-Johny Manu , Lussier Marc P. , Windisch Marc P. , Lolicato Marco , Lolli Marco Lucio , Vleminckx Margot , Caroleo Maria Cristina , Macias Maria J. , Valli Marilia , Barghash Marim M. , Mellado Mario , Tye Mark A. , Wilson Mark A. , Hannink Mark , Ashton Mark R. , Cerna Mark Vincent C.dela , Giorgis Marta , Safo Martin K. , Maurice Martin St. , McDowell Mary Ann , Pasquali Marzia , Mehedi Masfique , Serafim Mateus Sá Magalhães , Soellner Matthew B. , Alteen Matthew G. , Champion Matthew M. , Skorodinsky Maxim , O’Mara Megan L. , Bedi Mel , Rizzi Menico , Levin Michael , Mowat Michael , Jackson Michael R. , Paige Mikell , Al-Yozbaki Minnatallah , Giardini Miriam A. , Maksimainen Mirko M. , De Luise Monica , Hussain Muhammad Saddam , Christodoulides Myron , Stec Natalia , Zelinskaya Natalia , Van Pelt Natascha , Merrill Nathan M. , Singh Nathanael , Kootstra Neeltje A. , Singh Neeraj , Gandhi Neha S. , Chan Nei-Li , Trinh Nguyen Mai , Schneider Nicholas O. , Matovic Nick , Horstmann Nicola , Longo Nicola , Bharambe Nikhil , Rouzbeh Nirvan , Mahmoodi Niusha , Gumede Njabulo Joyfull , Anastasio Noelle C. , Khalaf Noureddine Ben , Rabal Obdulia , Kandror Olga , Escaffre Olivier , Silvennoinen Olli , Bishop Ozlem Tastan , Iglesias Pablo , Sobrado Pablo , Chuong Patrick , O’Connell Patrick , Martin-Malpartida Pau , Mellor Paul , Fish Paul V. , Moreira Paulo Otávio Lourenço , Zhou Pei , Liu Pengda , Liu Pengda , Wu Pengpeng , Agogo-Mawuli Percy , Jones Peter L. , Ngoi Peter , Toogood Peter , Ip Philbert , von Hundelshausen Philipp , Lee Pil H. , Rowswell-Turner Rachael B. , Balaña-Fouce Rafael , Rocha Rafael Eduardo Oliveira , Guido Rafael V. C. , Ferreira Rafaela Salgado , Agrawal Rajendra K. , Harijan Rajesh K. , Ramachandran Rajesh , Verma Rajkumar , Singh Rakesh K. , Tiwari Rakesh Kumar , Mazitschek Ralph , Koppisetti Rama K. , Dame Remus T. , Douville Renée N. , Austin Richard C. , Taylor Richard E. , Moore Richard G. , Ebright Richard H. , Angell Richard M. , Yan Riqiang , Kejriwal Rishabh , Batey Robert A. , Blelloch Robert , Vandenberg Robert J. , Hickey Robert J. , Kelm Robert J. , Lake Robert J. , Bradley Robert K. , Blumenthal Robert M. , Solano Roberto , Gierse Robin Matthias , Viola Ronald E. , McCarthy Ronan R. , Reguera Rosa Maria , Uribe Ruben Vazquez , do Monte-Neto Rubens Lima , Gorgoglione Ruggiero , Cullinane Ryan T. , Katyal Sachin , Hossain Sakib , Phadke Sameer , Shelburne Samuel A. , Geden Sandra E. , Johannsen Sandra , Wazir Sarah , Legare Scott , Landfear Scott M. , Radhakrishnan Senthil K. , Ammendola Serena , Dzhumaev Sergei , Seo Seung-Yong , Li Shan , Zhou Shan , Chu Shaoyou , Chauhan Shefali , Maruta Shinsaku , Ashkar Shireen R. , Shyng Show-Ling , Conticello Silvestro G. , Buroni Silvia , Garavaglia Silvia , White Simon J. , Zhu Siran , Tsimbalyuk Sofiya , Chadni Somaia Haque , Byun Soo Young , Park Soonju , Xu Sophia Q. , Banerjee Sourav , Zahler Stefan , Espinoza Stefano , Gustincich Stefano , Sainas Stefano , Celano Stephanie L. , Capuzzi Stephen J. , Waggoner Stephen N. , Poirier Steve , Olson Steven H. , Marx Steven O. , Van Doren Steven R. , Sarilla Suryakala , Brady-Kalnay Susann M. , Dallman Sydney , Azeem Syeda Maryam , Teramoto Tadahisa , Mehlman Tamar , Swart Tarryn , Abaffy Tatjana , Akopian Tatos , Haikarainen Teemu , Moreda Teresa Lozano , Ikegami Tetsuro , Teixeira Thaiz Rodrigues , Jayasinghe Thilina D. , Gillingwater Thomas H. , Kampourakis Thomas , Richardson Timothy I. , Herdendorf Timothy J. , Kotzé Timothy J. , O’Meara Timothy R. , Corson Timothy W. , Hermle Tobias , Ogunwa Tomisin Happy , Lan Tong , Su Tong , Banjo Toshihiro , O’Mara Tracy A. , Chou Tristan , Chou Tsui-Fen , Baumann Ulrich , Desai Umesh R. , Pai Vaibhav P. , Thai Van Chi , Tandon Vasudha , Banerji Versha , Robinson Victoria L. , Gunasekharan Vignesh , Namasivayam Vigneshwaran , Segers Vincent F. M. , Maranda Vincent , Dolce Vincenza , Maltarollo Vinícius Gonçalves , Scoffone Viola Camilla , Woods Virgil A. , Ronchi Virginia Paola , Van Hung Le Vuong , Clayton W. Brent , Lowther W. Todd , Houry Walid A. , Li Wei , Tang Weiping , Zhang Wenjun , Van Voorhis Wesley C. , Donaldson William A. , Hahn William C. , Kerr William G. , Gerwick William H. , Bradshaw William J. , Foong Wuen Ee , Blanchet Xavier , Wu Xiaoyang , Lu Xin , Qi Xin , Xu Xin , Yu Xinfang , Qin Xingping , Wang Xingyou , Yuan Xinrui , Zhang Xu , Zhang Yan Jessie , Hu Yanmei , Aldhamen Yasser Ali , Chen Yicheng , Li Yihe , Sun Ying , Zhu Yini , Gupta Yogesh K. , Pérez-Pertejo Yolanda , Li Yong , Tang Young , He Yuan , Tse-Dinh Yuk-Ching , Sidorova Yulia A. , Yen Yun , Li Yunlong , Frangos Zachary J. , Chung Zara , Su Zhengchen , Wang Zhenghe , Zhang Zhiguo , Liu Zhongle , Inde Zintis , Artía Zoraima , Heifets Abraham 
Published: April 2024

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.