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Increased pharmacological data and the rapid development of deep learning methods have enabled the construction of models to predict and screen drug pairs. However, the size of drug libraries is restricted to hundreds to thousands of compounds. The ScaffComb framework, which aims to bridge the gaps in the virtual screening of drug combinations in large\u2010scale databases, is proposed here. Inspired by phenotype\u2010based drug design, ScaffComb integrates phenotypic information into molecular scaffolds, which can be used to screen the drug library and identify potent drug combinations. First, ScaffComb is validated using the US food and drug administration dataset and known drug combinations are successfully reidentified. Then, ScaffComb is applied to screen the ZINC and ChEMBL databases, which yield novel drug combinations and reveal an ability to discover new synergistic mechanisms. To our knowledge, ScaffComb is the first method to use phenotype\u2010based virtual screening of drug combinations in large\u2010scale chemical datasets.<\/jats:p>","DOI":"10.1002\/advs.202102092","type":"journal-article","created":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T07:25:59Z","timestamp":1635751559000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["ScaffComb: A Phenotype\u2010Based Framework for Drug Combination Virtual Screening in Large\u2010Scale Chemical Datasets"],"prefix":"10.1002","volume":"8","author":[{"given":"Zhaofeng","family":"Ye","sequence":"first","affiliation":[{"name":"MOE Key Laboratory of Bioinformatics Bioinformatics Division Center for Synthetic and Systems Biology BNRist Department of Automation Tsinghua University  Beijing 100084 China"},{"name":"School of Medicine Tsinghua University  Beijing 100084 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengling","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Stem Cell Biology and Regenerative Medicine MOE Key Laboratory of Bioinformatics Tsinghua University  Beijing 100084 China"},{"name":"Tsinghua\u2010Peking Center for Life Sciences  Beijing 100084 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiangyang","family":"Zeng","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinformatics Bioinformatics Division Center for Synthetic and Systems Biology BNRist Department of Automation Tsinghua University  Beijing 100084 China"},{"name":"Institute for Interdisciplinary Information Sciences Tsinghua University  Beijing 100084 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1466-2294","authenticated-orcid":false,"given":"Juntao","family":"Gao","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinformatics Bioinformatics Division Center for Synthetic and Systems Biology BNRist Department of Automation Tsinghua University  Beijing 100084 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael Q.","family":"Zhang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Bioinformatics Bioinformatics Division Center for Synthetic and Systems Biology BNRist Department of Automation Tsinghua University  Beijing 100084 China"},{"name":"School of Medicine Tsinghua University  Beijing 100084 China"},{"name":"Department of Biological Sciences Center for Systems Biology The University of Texas at Dallas  Richardson TX 75080\u20103021 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,11]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(197501)35:1<98::AID-CNCR2820350115>3.0.CO;2-B"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3599"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11219"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2015.92"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2006.11.008"},{"key":"e_1_2_9_6_1","author":"Menden M. 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