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

doi:10.1021/acs.jmedchem.6b01340

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

Scripps Research Institute

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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 language	English
Pages (from-to)	10335-10341
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	22
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01340
State	Published - Nov 23 2016

Funding

We thank Prof. Ben Shen for access to a high-resolution mass spectrometer. This work was supported by NIH/NIDDK awards R01DK101871 (D.K.), F32DK097890 (T.H.), K99DK103116 (T.H.), R00DK103116 (T.H.), and F32DK108442 (R.B.), and AHA awards 12POST12050025 (T.H.) and 16POST27780018 (R.B.).

Funder number
K99DK103116, R01DK101871, F32DK108442, R00DK103116
F32DK097890
12POST12050025, 16POST27780018

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Hughes, T. S., Shang, J., Brust, R., De Vera, I. M. S., Fuhrmann, J., Ruiz, C., Cameron, M. D., Kamenecka, T. M., & Kojetin, D. J. (2016). 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. Journal of Medicinal Chemistry, 59(22), 10335-10341. https://doi.org/10.1021/acs.jmedchem.6b01340

Hughes, Travis S. ; Shang, Jinsai ; Brust, Richard et al. / 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. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 22. pp. 10335-10341.

@article{ffd71394cc7647a4a689b42671d8b045,

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.",

author = "Hughes, \{Travis S.\} and Jinsai Shang and Richard Brust and \{De Vera\}, \{Ian Mitchelle S.\} and Jakob Fuhrmann and Claudia Ruiz and Cameron, \{Michael D.\} and Kamenecka, \{Theodore M.\} and Kojetin, \{Douglas J.\}",

note = "Publisher Copyright: {\textcopyright} 2016 American Chemical Society.",

year = "2016",

month = nov,

day = "23",

doi = "10.1021/acs.jmedchem.6b01340",

language = "English",

volume = "59",

pages = "10335--10341",

journal = "Journal of Medicinal Chemistry",

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Hughes, TS, Shang, J, Brust, R, De Vera, IMS, Fuhrmann, J, Ruiz, C, Cameron, MD, Kamenecka, TM & Kojetin, DJ 2016, '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', Journal of Medicinal Chemistry, vol. 59, no. 22, pp. 10335-10341. https://doi.org/10.1021/acs.jmedchem.6b01340

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. / Hughes, Travis S.; Shang, Jinsai; Brust, Richard et al.
In: Journal of Medicinal Chemistry, Vol. 59, No. 22, 23.11.2016, p. 10335-10341.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Hughes, Travis S.

AU - Shang, Jinsai

AU - Brust, Richard

AU - De Vera, Ian Mitchelle S.

AU - Fuhrmann, Jakob

AU - Ruiz, Claudia

AU - Cameron, Michael D.

AU - Kamenecka, Theodore M.

AU - Kojetin, Douglas J.

PY - 2016/11/23

Y1 - 2016/11/23

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84999885189

U2 - 10.1021/acs.jmedchem.6b01340

DO - 10.1021/acs.jmedchem.6b01340

M3 - Article

C2 - 27783520

AN - SCOPUS:84999885189

SN - 0022-2623

VL - 59

SP - 10335

EP - 10341

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 22

ER -

Hughes TS, Shang J, Brust R, De Vera IMS, Fuhrmann J, Ruiz C et al. 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. Journal of Medicinal Chemistry. 2016 Nov 23;59(22):10335-10341. doi: 10.1021/acs.jmedchem.6b01340

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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