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We screened the Enamine high-throughput collection of 2.1 million compounds, selecting 39 compounds for testing, with the most potent binding with a 130 \u03bcM median inhibitory concentration (IC\n            <jats:sub>50<\/jats:sub>\n            ). We then paired FrankenROCS with an active learning algorithm (Thompson sampling) to efficiently search the Enamine REAL database of 22 billion molecules, testing 32 compounds with the most potent binding with a 220 \u03bcM IC\n            <jats:sub>50<\/jats:sub>\n            . Further optimization led to analogs with IC\n            <jats:sub>50<\/jats:sub>\n            values better than 10 \u03bcM. This lead series has improved membrane permeability and is poised for optimization. FrankenROCS is a scalable method for fragment linking to exploit synthesis-on-demand libraries.\n          <\/jats:p>","DOI":"10.1126\/sciadv.ads7187","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T17:58:47Z","timestamp":1748455127000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":26,"title":["Exploration of structure-activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment linking and active learning"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5155-7325","authenticated-orcid":true,"given":"Galen J.","family":"Correy","sequence":"first","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA 94158, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3671-8885","authenticated-orcid":true,"given":"Moira M.","family":"Rachman","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0243-0760","authenticated-orcid":true,"given":"Takaya","family":"Togo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3115-9757","authenticated-orcid":true,"given":"Stefan","family":"Gahbauer","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3388-7803","authenticated-orcid":true,"given":"Yagmur U.","family":"Doruk","sequence":"additional","affiliation":[{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9732-0349","authenticated-orcid":true,"given":"Maisie G. V.","family":"Stevens","sequence":"additional","affiliation":[{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2013-8941","authenticated-orcid":true,"given":"Priyadarshini","family":"Jaishankar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Kelley","sequence":"additional","affiliation":[{"name":"Relay Therapeutics, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6465-6959","authenticated-orcid":true,"given":"Brian","family":"Goldman","sequence":"additional","affiliation":[{"name":"Relay Therapeutics, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Relay Therapeutics, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5932-7406","authenticated-orcid":true,"given":"Trevor","family":"Kramer","sequence":"additional","affiliation":[{"name":"Relay Therapeutics, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5444-7754","authenticated-orcid":true,"given":"Dmytro S.","family":"Radchenko","sequence":"additional","affiliation":[{"name":"Enamine Ltd., Kyiv, Ukraine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6073-002X","authenticated-orcid":true,"given":"Yurii S.","family":"Moroz","sequence":"additional","affiliation":[{"name":"Enamine Ltd., Kyiv, Ukraine."},{"name":"Chemspace LLC, Kyiv, Ukraine."},{"name":"Department of Chemistry, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1446-7878","authenticated-orcid":true,"given":"Alan","family":"Ashworth","sequence":"additional","affiliation":[{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0797-0272","authenticated-orcid":true,"given":"Patrick","family":"Riley","sequence":"additional","affiliation":[{"name":"Relay Therapeutics, Cambridge, MA 02142, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6098-7367","authenticated-orcid":true,"given":"Brian K.","family":"Shoichet","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1240-2846","authenticated-orcid":true,"given":"Adam R.","family":"Renslo","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2860-7958","authenticated-orcid":true,"given":"W. 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