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This work offers solutions to the long\u2010standing problem of false positives caused by SCAMs in high\u2010throughput screening for drug discovery and demonstrates the power of xAI in the classification of molecular properties that are not chemically intuitive based on our current understanding. We leverage xAI insights and molecular counterfactuals to design alternatives to problematic compounds in drug screening libraries. Additionally, we experimentally validate the MEGAN prediction classification for one of the counterfactuals and demonstrate the utility of counterfactuals for altering the aggregation properties of a compound through minor structural modifications. The integration of this method in high\u2010throughput screening approaches will help combat and circumvent false positives, providing better lead molecules more rapidly and thus accelerating drug discovery cycles.<\/jats:p>","DOI":"10.1002\/anie.202503259","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T05:48:09Z","timestamp":1747633689000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mitigating Molecular Aggregation in Drug Discovery With Predictive Insights From Explainable AI"],"prefix":"10.1002","volume":"64","author":[{"given":"Hunter","family":"Sturm","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Manitoba  Winnipeg Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Teufel","sequence":"additional","affiliation":[{"name":"Institute of Theoretical Informatics Karlsruhe Institute of Technology  Karlsruhe Germany"},{"name":"Institute of Nanotechnology Karlsruhe Institute of Technology  Karlsruhe Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlin A.","family":"Isfeld","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Manitoba  Winnipeg Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Friederich","sequence":"additional","affiliation":[{"name":"Institute of Theoretical Informatics Karlsruhe Institute of Technology  Karlsruhe Germany"},{"name":"Institute of Nanotechnology Karlsruhe Institute of Technology  Karlsruhe Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0679-6025","authenticated-orcid":false,"given":"Rebecca L.","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Chemistry University of Manitoba  Winnipeg Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1010613"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06887-8"},{"key":"e_1_2_8_3_1","first-page":"149","volume":"11","author":"Klumpp M.","year":"2016","journal-title":"Drug Discov."},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2010.03.020"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2020.01.014"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja802977h"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.5b00263"},{"key":"e_1_2_8_8_1","volume":"2","author":"Lee K.","year":"2021","journal-title":"Cell Rep. 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