Probing the Complex Binding Modes of the PPARγ Partial Agonist 2-Chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide (T2384) to Orthosteric and Allosteric Sites with NMR Spectroscopy

Travis S. Hughes, Jinsai Shang, Richard Brust, Ian Mitchelle S. De Vera, Jakob Fuhrmann, Claudia Ruiz, Michael D. Cameron, Theodore M. Kamenecka, Douglas J. Kojetin

Research output: Contribution to journalArticlepeer-review

Abstract

In a previous study, a cocrystal structure of PPARγ bound to 2-chloro-N-(3-chloro-4-((5-chlorobenzo[d]thiazol-2-yl)thio)phenyl)-4-(trifluoromethyl)benzenesulfonamide (1, T2384) revealed two orthosteric pocket binding modes attributed to a concentration-dependent biochemical activity profile. However, 1 also bound an alternate/allosteric site that could alternatively account for the profile. Here, we show ligand aggregation afflicts the activity profile of 1 in biochemical assays. However, ligand-observed fluorine (19F) and protein-observed NMR confirms 1 binds PPARγ with two orthosteric binding modes and to an allosteric site.

Original languageEnglish
Pages (from-to)10335-10341
Number of pages7
JournalJournal of Medicinal Chemistry
Volume59
Issue number22
DOIs
StatePublished - Nov 23 2016

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