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

18 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

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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",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "22",

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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.

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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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