title: 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.
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.
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458.
authors: Travis S
authors: TS
authors: Hughes
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458.
authors: Jinsai
authors: J
authors: Shang
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458.
authors: Richard
authors: R
authors: Brust
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458.
authors: Ian Mitchelle S
authors: IMS
authors: de Vera
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458.
authors: Jakob
authors: J
authors: Fuhrmann
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458.
authors: Claudia
authors: C
authors: Ruiz
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458.
authors: Michael D
authors: MD
authors: Cameron
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458.
authors: Theodore M
authors: TM
authors: Kamenecka
authors: Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458.
authors: Douglas J
authors: DJ
authors: Kojetin
mesh_terms: D000495:Allosteric Site / Q000187:drug effects*; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D047495:PPAR gamma / Q000819:agonists*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D052160:Benzothiazoles; D008024:Ligands; D047495:PPAR gamma; D013449:Sulfonamides; C529047:T2384; D000096926:Benzenesulfonamides