AI-Enhanced Adaptive Virtual Screening Platform Enabling Exploration of 69 Billion Molecules Discovers Structurally Validated FSP1 Inhibitors

AI-Enhanced Adaptive Virtual Screening Platform Enabling Exploration of 69 Billion Molecules Discovers Structurally Validated FSP1 Inhibitors | bioRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search New Results AI-Enhanced Adaptive Virtual Screening Platform Enabling Exploration of 69 Billion Molecules Discovers Structurally Validated FSP1 Inhibitors Domiziana Cecchini , AkshatKumar Nigam , Ming Tang , Joana Reis , Matt Koop , Andrea Gottinger , Callum Robert Nicoll , Yao Wang , Abhilash Jayaraj , Süleyman Selim Çınaroğlu , Ricarda Törner , Yehor Malets , Minko Gehev , Krishna M. Padmanabha Das , Kelly Churion , Jongwan Kim , Nidhin Thomas , Yong Li , Hyuk-Soo Seo , Sirano Dhe-Paganon , Christopher Secker , Mohammad Haddadnia , Alexander Hasson , Minkai Li , Abhishek Kumar , Roni Levin-Konigsberg , Eun-Bee Choi , Geoffrey I. Shapiro , Huel Cox 3rd , Luke Sebastian , Chelsea Braithwaite , Puspalata Bashyal , Dmytro S. Radchenko , Aditya Kumar , Lei Yang , Pierre-Yves Aquilanti , Henry Gabb , Amr Alhossary , Gerhard Wagner , Alán Aspuru-Guzik , Yurii S. Moroz , Charalampos G. Kalodimos , Konstantin Fackeldey , John D. Schuetz , View ORCID Profile Andrea Mattevi , Haribabu Arthanari , View ORCID Profile Christoph Gorgulla doi: https://doi.org/10.1101/2023.04.25.537981 Domiziana Cecchini 1 Department of Biology and Biotechnology, University of Pavia , Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site AkshatKumar Nigam 2 Klyne , San Francisco, USA 3 Department of Computer Science, Stanford University , Stanford, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ming Tang 4 The University of Queensland, Frazer Institute, Faculty of Medicine at the Translational Research Institute Australia , Brisbane, Australia 5 Queensland University of Technology, School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute Australia , Brisbane, Australia 6 Department of Structural Biology, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joana Reis 7 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Matt Koop 8 Amazon Web Services , Seattle, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrea Gottinger 1 Department of Biology and Biotechnology, University of Pavia , Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Callum Robert Nicoll 1 Department of Biology and Biotechnology, University of Pavia , Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yao Wang 9 Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abhilash Jayaraj 10 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University , Boston, USA 7 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Süleyman Selim Çınaroğlu 11 Department of Biochemistry, University of Oxford , UK 12 Department of Bioengineering, Ege University , Bornova, 35040, Türkiye Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ricarda Törner 7 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, USA 13 Department of Chemistry, University of Zurich , Switzerland Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yehor Malets 14 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine , Kyiv, Ukraine Find this author on Google Scholar Find this author on PubMed Search for this author on this site Minko Gehev 15 Google, Mountain View , USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Krishna M. Padmanabha Das 10 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University , Boston, USA 6 Department of Structural Biology, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kelly Churion 6 Department of Structural Biology, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jongwan Kim 6 Department of Structural Biology, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nidhin Thomas 6 Department of Structural Biology, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yong Li 16 Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hyuk-Soo Seo 7 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sirano Dhe-Paganon 7 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Christopher Secker 17 Zuse Institute Berlin (ZIB) , Berlin, Germany 18 Max Delbrück Center for Molecular Medicine , Berlin, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mohammad Haddadnia 19 Department of Molecular Genetics, University of Toronto , Toronto, Canada 10 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University , Boston, USA 7 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alexander Hasson 20 Department of Oncology, University of Oxford , Oxford, UK 21 Mathematical Institute, University of Oxford , Oxford, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Minkai Li 22 Harvard College , Cambridge, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abhishek Kumar 23 Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati , India 6 Department of Structural Biology, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Roni Levin-Konigsberg 2 Klyne , San Francisco, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Eun-Bee Choi 24 Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Geoffrey I. Shapiro 24 Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Huel Cox 3rd 7 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Luke Sebastian 7 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Chelsea Braithwaite 7 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Puspalata Bashyal 7 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dmytro S. Radchenko 25 Enamine Ltd , Kyiv, Ukraine Find this author on Google Scholar Find this author on PubMed Search for this author on this site Aditya Kumar 26 Institute for Mathematics, Technical University Berlin , Berlin, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Lei Yang 16 Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Pierre-Yves Aquilanti 8 Amazon Web Services , Seattle, USA 27 NVIDIA , Santa Clara, CA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Henry Gabb 28 Intel , Santa Clara, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Amr Alhossary 29 Wesleyan University , Middletown, USA 30 Pulse for Integrated Solutions GmbH, Unterschleißheim , Bavaria, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gerhard Wagner 10 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University , Boston, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alán Aspuru-Guzik 31 Department of Computer Science, University of Toronto , Toronto, Ontario, Canada 32 Vector Institute for Artificial Intelligence , Toronto, Ontario, Canada 33 Department of Chemistry, University of Toronto , Toronto, Ontario, Canada 34 Canadian Institute for Advanced Research , Toronto, Ontario, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yurii S. Moroz 25 Enamine Ltd , Kyiv, Ukraine 35 Chemspace LLC , Kyiv, Ukraine 36 Taras Shevchenko National University of Kyiv , Kyiv, Ukraine Find this author on Google Scholar Find this author on PubMed Search for this author on this site Charalampos G. Kalodimos 6 Department of Structural Biology, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Konstantin Fackeldey 17 Zuse Institute Berlin (ZIB) , Berlin, Germany 26 Institute for Mathematics, Technical University Berlin , Berlin, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site John D. Schuetz 9 Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrea Mattevi 1 Department of Biology and Biotechnology, University of Pavia , Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Andrea Mattevi For correspondence: christoph.gorgulla{at}stjude.org andrea.mattevi{at}unipv.it hari{at}hms.harvard.edu Haribabu Arthanari 10 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University , Boston, USA 7 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: christoph.gorgulla{at}stjude.org andrea.mattevi{at}unipv.it hari{at}hms.harvard.edu Christoph Gorgulla 6 Department of Structural Biology, St. Jude Children’s Research Hospital , Memphis, Tennessee, USA 10 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University , Boston, USA 37 Department of Physics, Faculty of Arts and Sciences, Harvard University , Cambridge, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Christoph Gorgulla For correspondence: christoph.gorgulla{at}stjude.org andrea.mattevi{at}unipv.it hari{at}hms.harvard.edu Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Identifying potent lead molecules for specific targets remains a major bottleneck in drug discovery. As structural information about proteins becomes increasingly available, ultra-large virtual screenings (ULVSs) which computationally evaluate billions of molecules offer a powerful way to accelerate early-stage drug discovery. Here, we introduce AdaptiveFlow, an open-source platform designed to make ULVSs more accessible, scalable, and efficient. AdaptiveFlow provides free access to a screening-ready version of the Enamine REAL Space ( 1 ), the largest library of ready-to-dock, drug-like molecules, containing 69 billion compounds that we prepared using the ligand preparation module of the platform. A key innovation of the platform is its use of a multi-dimensional grid of molecular properties, which helps researchers explore and prioritize chemical space more effectively and reduce the computational costs by a factor of approximately 1000. This grid forms the basis of a new method for identifying promising regions of chemical space, enabling systematic exploration and prioritization of compound libraries. An optional active learning component can further accelerate this process by adaptively steering the search toward molecules most likely to bind a given target. To support a broad range of applications, AdaptiveFlow is compatible with over 1,500 docking protocols. The platform achieves near-linear scaling on up to 5.6 million CPUs in the AWS Cloud, setting a new benchmark for large-scale cloud computing in drug discovery. Using this approach, we identified nanomolar inhibitors of two disease-relevant targets: ferroptosis suppressor protein 1 (FSP1) and poly(ADP-ribose) polymerase 1 (PARP-1) ( 2 , 3 ). By leveraging newly solved crystal structures of FSP1 in complex with NAD + , FAD, and coenzyme Q 1 , we validated these hits experimentally and determined the co-crystal structures of FSP1 bound to small-molecule inhibitors, enabling insights into inhibitor binding mechanisms previously unknown. With its high scalability, flexibility, and open accessibility, AdaptiveFlow offers a powerful new resource for discovering and optimizing drug candidates at an unprecedented scale and speed. Competing Interest Statement The authors declare the following competing interests: D.S.R. works for Enamine, a company that is involved in the synthesis and distribution of drug-like compounds. Y.S.M is a scientific advisor to Chemspace LLC and VP of Sales and Marketing at Enamine Ltd. C.G. and G.W. are cofounders of Virtual Discovery Inc., which is a fee-for-service company for computational drug discovery. M.G. works for Google, a company providing cloud computing services. M.K. and P.-Y.A. work for Amazon Web Services, a company providing cloud computing services. Footnotes Additional benchmark results. Additional experimental results. Revised manuscript text. https://adaptive-flow.ai/ https://github.com/QuantumAI4Bio Funder Information Declared MATH+ (EXC-2046/1) , 390685689 Bio-X Stanford Interdisciplinary Graduate Fellowship (SGIF) European Research Council , 101094471 Associazione Italiana per la Ricerca sul Cancro (AIRC) , 28754 NIH , GM136859 , GM158220 Dana-Farber Cancer Institute, https://ror.org/02jzgtq86 American Lebanese Syrian Associated Charities, https://ror.org/03rx10x31 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license . Back to top Previous Next Posted March 23, 2026. 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Schuetz , Andrea Mattevi , Haribabu Arthanari , Christoph Gorgulla bioRxiv 2023.04.25.537981; doi: https://doi.org/10.1101/2023.04.25.537981 Share This Article: Copy Citation Tools AI-Enhanced Adaptive Virtual Screening Platform Enabling Exploration of 69 Billion Molecules Discovers Structurally Validated FSP1 Inhibitors Domiziana Cecchini , AkshatKumar Nigam , Ming Tang , Joana Reis , Matt Koop , Andrea Gottinger , Callum Robert Nicoll , Yao Wang , Abhilash Jayaraj , Süleyman Selim Çınaroğlu , Ricarda Törner , Yehor Malets , Minko Gehev , Krishna M. Padmanabha Das , Kelly Churion , Jongwan Kim , Nidhin Thomas , Yong Li , Hyuk-Soo Seo , Sirano Dhe-Paganon , Christopher Secker , Mohammad Haddadnia , Alexander Hasson , Minkai Li , Abhishek Kumar , Roni Levin-Konigsberg , Eun-Bee Choi , Geoffrey I. Shapiro , Huel Cox 3rd , Luke Sebastian , Chelsea Braithwaite , Puspalata Bashyal , Dmytro S. Radchenko , Aditya Kumar , Lei Yang , Pierre-Yves Aquilanti , Henry Gabb , Amr Alhossary , Gerhard Wagner , Alán Aspuru-Guzik , Yurii S. Moroz , Charalampos G. Kalodimos , Konstantin Fackeldey , John D. Schuetz , Andrea Mattevi , Haribabu Arthanari , Christoph Gorgulla bioRxiv 2023.04.25.537981; doi: https://doi.org/10.1101/2023.04.25.537981 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Bioinformatics Subject Areas All Articles Animal Behavior and Cognition (8003) Biochemistry (18709) Bioengineering (14841) Bioinformatics (44364) Biophysics (22561) Cancer Biology (19682) Cell Biology (26845) Clinical Trials (138) Developmental Biology (13943) Ecology (20970) Epidemiology (2067) Evolutionary Biology (25415) Genetics (16151) Genomics (23478) Immunology (18681) Microbiology (42421) Molecular Biology (18022) Neuroscience (93355) Paleontology (699) Pathology (2977) Pharmacology and Toxicology (5086) Physiology (8105) Plant Biology (15969) Scientific Communication and Education (2094) Synthetic Biology (4549) Systems Biology (10219) Zoology (2384)

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