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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.
null, n., Wallach, I., Bernard, D., Nguyen, K., Ho, G., Morrison, A., et al. (2024). AI is a viable alternative to high throughput screening: a 318-target study. SCIENTIFIC REPORTS, 14(1), 1-16 [10.1038/s41598-024-54655-z].
AI is a viable alternative to high throughput screening: a 318-target study
null, null;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;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
2024
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.
null, n., Wallach, I., Bernard, D., Nguyen, K., Ho, G., Morrison, A., et al. (2024). AI is a viable alternative to high throughput screening: a 318-target study. SCIENTIFIC REPORTS, 14(1), 1-16 [10.1038/s41598-024-54655-z].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/966963
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