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This discovery provides a set of three structural handles for further structure\u2010activity relationship (SAR) studies of this potent microtubule\u2010stabilizing agent. Moreover, it provides additional evidence of the complex relationship between ligand preorganization, conformational flexibility, and biological potency. In contrast to medicinal chemistry dogma, these results demonstrate that increased overall conformational flexibility is not necessarily detrimental to protein binding affinity and biological activity.<\/jats:p>","DOI":"10.1002\/cmdc.202300292","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T11:16:51Z","timestamp":1691493411000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Linear (\u2212)\u2010Zampanolide: Flexibility in Conformation\u2013Activity Relationships"],"prefix":"10.1002","volume":"18","author":[{"given":"Christian A.","family":"Uma\u00f1a","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry and the Warren Center for Drug Discovery University of Notre Dame  Notre Dame IN 46556\u20135670 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey 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