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Here we report a detailed experimental and computational study of the drug target, human heat shock protein 90, to explore the contribution of protein dynamics to the binding thermodynamics and kinetics of drug-like compounds. We observe that their binding properties depend on whether the protein has a loop or a helical conformation in the binding site of the ligand-bound state. Compounds bound to the helical conformation display slow association and dissociation rates, high-affinity and high cellular efficacy, and predominantly entropically driven binding. An important entropic contribution comes from the greater flexibility of the helical relative to the loop conformation in the ligand-bound state. This unusual mechanism suggests increasing target flexibility in the bound state by ligand design as a new strategy for drug discovery.<\/jats:p>","DOI":"10.1038\/s41467-017-02258-w","type":"journal-article","created":{"date-parts":[[2017,12,18]],"date-time":"2017-12-18T10:03:16Z","timestamp":1513591396000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":258,"title":["Protein conformational flexibility modulates kinetics and thermodynamics of drug binding"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3503-9963","authenticated-orcid":false,"given":"M.","family":"Amaral","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4687-6572","authenticated-orcid":false,"given":"D. 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