Domiziana Cecchini, AkshatKumar Nigam, Ming Tang, Joana Reis, Matt Koop, Andrea Gottinger, Callum Robert Nicoll, Yao Wang, Abhilash Jayaraj, Süleyman Selim Çınaroglu, 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, Luke Sebastian, Chelsea Braithwaite, Puspalata Bashyal, Dmytro S Radchenko, Aditya Kumar, Lei Yang, Pierre-Yves Aquilanti, Henry Gabb, Amr Alhossary, Eric O'Neill, Gerhard Wagner, Alán Aspuru-Guzik, Yurii S Moroz, Charalampos G Kalodimos, Konstantin Fackeldey, John D Schuetz, Andrea Mattevi, Haribabu Arthanari, Christoph Gorgulla
Ultralarge virtual screenings (ULVSs) evaluate billions of molecules for drug discovery but face cost, flexibility and scalability limits. We introduce AdaptiveFlow, an open-source platform that makes ULVSs more accessible, scalable and efficient and supports artificial intelligence (AI) and machine learning (ML) method development. AdaptiveFlow provides a screening-ready version of the Enamine REAL Space, to our knowledge the largest library of ready-to-dock, drug-like molecules, comprising 69 billion compounds, also available in SELFIES format. An 18-dimensional grid of molecular properties prioritizes promising chemical subspaces, with optional active learning, reducing computational costs by orders of magnitude. AdaptiveFlow integrates >1,500 docking protocols, including GPU-accelerated and ML-based methods, and achieves near-linear scaling on up to 5.6 million CPUs in the Amazon Web Services cloud. We identified nanomolar inhibitors of two disease-relevant targets, ferroptosis suppressor protein 1 (FSP1) and poly(ADP-ribose) polymerase 1. Co-crystal structures provided mechanistic insights into FSP1 inhibition. AdaptiveFlow enables drug discovery at unprecedented scale and supports the development of AI-driven methods.