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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Hughes TS,Shang J,Brust R,de Vera IMS,Fuhrmann J,Ruiz C,Cameron MD,Kamenecka TM,Kojetin DJdoi
10.1021/acs.jmedchem.6b01340subject
Has Abstractpub_date
2016-11-23 00:00:00pages
10335-10341issue
22eissn
0022-2623issn
1520-4804journal_volume
59pub_type
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