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The approach is demonstrated by first screening a curated fragment library using <jats:sup>19<\/jats:sup>F NMR to discover a quality binder to ACE2, the human receptor required for entry and infection by the SARS\u2010CoV\u20102 virus. Based on this binder, a highly related scaffold was derived and used as a \u201csmart scaffold\u201d or template in a computer\u2010aided finger\u2010print search of a library of FDA\u2010approved or marketed drugs. The most interesting structural match involved the drug vortioxetine which was then experimentally shown by NMR spectroscopy to bind directly to human ACE2. Also, an ELISA assay showed that the drug inhibits the interaction of human ACE2 to the SARS\u2010CoV\u20102 receptor\u2010binding\u2010domain (RBD). Moreover, our cell\u2010culture infectivity assay confirmed that vortioxetine is active against SARS\u2010CoV\u20102 and inhibits viral replication. Thus, the use of \u201csmart scaffolds\u201d based on binders from fragment screens may have general utility for identifying candidates of FDA\u2010approved or marketed drugs as a rapid repurposing strategy. Similar approaches can be envisioned for other fields involving small\u2010molecule chemical applications.<\/jats:p>","DOI":"10.1002\/cmdc.202200092","type":"journal-article","created":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T13:40:37Z","timestamp":1647524437000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Jumping from Fragment to Drug via Smart Scaffolds"],"prefix":"10.1002","volume":"17","author":[{"given":"Majid D.","family":"Farahani","sequence":"first","affiliation":[{"name":"Centre Armand-Frappier Sant\u00e9 Biotechnologie Universit\u00e9 de Qu\u00e9bec, INRS  531 boulevard des Prairies Laval Qu\u00e9bec, H7V 1B7 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanos C. 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