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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\u2009million 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\u2009billion 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 effect.<\/jats:p>","DOI":"10.1038\/s43588-025-00777-x","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T10:03:31Z","timestamp":1741860211000},"page":"301-312","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Rapid traversal of vast chemical space using machine learning-guided docking screens"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2915-7901","authenticated-orcid":false,"given":"Andreas","family":"Luttens","sequence":"first","affiliation":[]},{"given":"Israel","family":"Cabeza de Vaca","sequence":"additional","affiliation":[]},{"given":"Leonard","family":"Sparring","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9","family":"Brea","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1595-3459","authenticated-orcid":false,"given":"Ant\u00f3n Leandro","family":"Mart\u00ednez","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7744-1491","authenticated-orcid":false,"given":"Nour Aldin","family":"Kahlous","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5444-7754","authenticated-orcid":false,"given":"Dmytro S.","family":"Radchenko","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6073-002X","authenticated-orcid":false,"given":"Yurii S.","family":"Moroz","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4730-0863","authenticated-orcid":false,"given":"Mar\u00eda Isabel","family":"Loza","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3107-331X","authenticated-orcid":false,"given":"Ulf","family":"Norinder","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4623-2977","authenticated-orcid":false,"given":"Jens","family":"Carlsson","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,3,13]]},"reference":[{"key":"777_CR1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1002\/(SICI)1098-1128(199601)16:1<3::AID-MED1>3.0.CO;2-6","volume":"16","author":"RS Bohacek","year":"1996","unstructured":"Bohacek, R. 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