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

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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 ( 19 F) and protein-observed NMR confirms 1 binds PPARγ with two orthosteric binding modes and to an allosteric site.