Luttens, AndreasCabeza de Vaca, IsraelSparring, LeonardBrea Floriani, José ManuelMartínez Rodríguez, Antón LeandroKahlous, Nour AldinRadchenko, Dmytro S.Moroz, Yurii S.Loza García, María IsabelNorinder, UlfCarlsson, Jens2026-01-292026-01-292025-03-13Luttens, A., Cabeza de Vaca, I., Sparring, L. et al. Rapid traversal of vast chemical space using machine learning-guided docking screens. Nat Comput Sci 5, 301–312 (2025). https://doi.org/10.1038/s43588-025-00777-xhttps://hdl.handle.net/10347/45594The accelerating growth of make-on-demand chemical libraries provides unprecedented opportunities to identify starting points for drug discovery with virtual screening. However, these multi-billion-scale libraries are challenging to screen, even for the fastest structure-based docking methods. Here we explore a strategy that combines machine learning and molecular docking to enable rapid virtual screening of databases containing billions of compounds. In our workflow, a classification algorithm is trained to identify top-scoring compounds based on molecular docking of 1 million compounds to the target protein. The conformal prediction framework is then used to make selections from the multi-billion-scale library, reducing the number of compounds to be scored by docking. The CatBoost classifier showed an optimal balance between speed and accuracy and was used to adapt the workflow for screens of ultralarge libraries. Application to a library of 3.5 billion compounds demonstrated that our protocol can reduce the computational cost of structure-based virtual screening by more than 1,000-fold. Experimental testing of predictions identified ligands of G protein-coupled receptors and demonstrated that our approach enables discovery of compounds with multi-target activity tailored for therapeutic effecteng© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International LicenseAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/CheminformaticsComputational chemistryMachine learningStructure-based drug designVirtual drug screeningjournal article10.1038/s43588-025-00777-x2662-8457open access