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

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