Structure–activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359

Hang Zhang; Alexander L. Nielsen; Michael W. Boesgaard; Kasper Harpsøe; Norelle L. Daly; Xiao-feng Xiong; Christina R. Underwood; Linda M. Haugaard-kedström; Hans Bräuner-osborne; David E. Gloriam; Kristian Strømgaard

doi:10.1016/j.ejmech.2018.07.023

Structure–activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359

Hang Zhang, Alexander L. Nielsen, Michael W. Boesgaard, Kasper Harpsøe, Norelle L. Daly, Xiao-feng Xiong, Christina R. Underwood, Linda M. Haugaard-kedström, Hans Bräuner-osborne, David E. Gloriam, Kristian Strømgaard

7 Citations (Scopus)

Abstract

G proteins are key mediators in the signaling of G protein-coupled receptors and involved in a plethora of important physiological processes. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known selective inhibitors of the Gq protein subfamily. So far, all reported YM-254890 and FR900359 analogs show no inhibition of other G protein subtypes except the Gq, G11 and G14 proteins. Here we report the rationalization of the high potency of FR900359 and efforts towards understanding the G protein subtype selectivity by synthesis of a collection of structurally and stereochemically diverse analogs of YM-254890 using an efficient synthetic protocol. We performed the first conformational study of YM-254890 in aqueous solution by NMR spectroscopy and replica exchange molecular dynamics, which suggested that the combined contribution of residues with appropriate size, stereochemistry and conformational stability are critical for inhibitory potency. Moreover, in addition to the fit of the binding pocket, more factors should be taken into consideration for the development of compounds targeting other G proteins.

Original language	English
Journal	European Journal of Medicinal Chemistry
Volume	156
Pages (from-to)	847-860
ISSN	0223-5234
DOIs	https://doi.org/10.1016/j.ejmech.2018.07.023
Publication status	Published - 5 Aug 2018

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10.1016/j.ejmech.2018.07.023

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Zhang, H., Nielsen, A. L., Boesgaard, M. W., Harpsøe, K., Daly, N. L., Xiong, X., Underwood, C. R., Haugaard-kedström, L. M., Bräuner-osborne, H., Gloriam, D. E., & Strømgaard, K. (2018). Structure–activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359. European Journal of Medicinal Chemistry, 156, 847-860. https://doi.org/10.1016/j.ejmech.2018.07.023

Zhang, H, Nielsen, AL, Boesgaard, MW, Harpsøe, K, Daly, NL, Xiong, X, Underwood, CR, Haugaard-kedström, LM, Bräuner-osborne, H , Gloriam, DE & Strømgaard, K 2018, 'Structure–activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359', European Journal of Medicinal Chemistry, vol. 156, pp. 847-860. https://doi.org/10.1016/j.ejmech.2018.07.023

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title = "Structure–activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359",

abstract = "G proteins are key mediators in the signaling of G protein-coupled receptors and involved in a plethora of important physiological processes. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known selective inhibitors of the Gq protein subfamily. So far, all reported YM-254890 and FR900359 analogs show no inhibition of other G protein subtypes except the Gq, G11 and G14 proteins. Here we report the rationalization of the high potency of FR900359 and efforts towards understanding the G protein subtype selectivity by synthesis of a collection of structurally and stereochemically diverse analogs of YM-254890 using an efficient synthetic protocol. We performed the first conformational study of YM-254890 in aqueous solution by NMR spectroscopy and replica exchange molecular dynamics, which suggested that the combined contribution of residues with appropriate size, stereochemistry and conformational stability are critical for inhibitory potency. Moreover, in addition to the fit of the binding pocket, more factors should be taken into consideration for the development of compounds targeting other G proteins.",

author = "Hang Zhang and Nielsen, {Alexander L.} and Boesgaard, {Michael W.} and Kasper Harps{\o}e and Daly, {Norelle L.} and Xiao-feng Xiong and Underwood, {Christina R.} and Haugaard-kedstr{\"o}m, {Linda M.} and Hans Br{\"a}uner-osborne and Gloriam, {David E.} and Kristian Str{\o}mgaard",

year = "2018",

month = aug,

day = "5",

doi = "10.1016/j.ejmech.2018.07.023",

language = "English",

volume = "156",

pages = "847--860",

journal = "European Journal of Medicinal Chemistry",

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TY - JOUR

T1 - Structure–activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359

AU - Zhang, Hang

AU - Nielsen, Alexander L.

AU - Boesgaard, Michael W.

AU - Harpsøe, Kasper

AU - Daly, Norelle L.

AU - Xiong, Xiao-feng

AU - Underwood, Christina R.

AU - Haugaard-kedström, Linda M.

AU - Bräuner-osborne, Hans

AU - Gloriam, David E.

AU - Strømgaard, Kristian

PY - 2018/8/5

Y1 - 2018/8/5

N2 - G proteins are key mediators in the signaling of G protein-coupled receptors and involved in a plethora of important physiological processes. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known selective inhibitors of the Gq protein subfamily. So far, all reported YM-254890 and FR900359 analogs show no inhibition of other G protein subtypes except the Gq, G11 and G14 proteins. Here we report the rationalization of the high potency of FR900359 and efforts towards understanding the G protein subtype selectivity by synthesis of a collection of structurally and stereochemically diverse analogs of YM-254890 using an efficient synthetic protocol. We performed the first conformational study of YM-254890 in aqueous solution by NMR spectroscopy and replica exchange molecular dynamics, which suggested that the combined contribution of residues with appropriate size, stereochemistry and conformational stability are critical for inhibitory potency. Moreover, in addition to the fit of the binding pocket, more factors should be taken into consideration for the development of compounds targeting other G proteins.

AB - G proteins are key mediators in the signaling of G protein-coupled receptors and involved in a plethora of important physiological processes. The natural product cyclic depsipeptides YM-254890 and FR900359 are the only known selective inhibitors of the Gq protein subfamily. So far, all reported YM-254890 and FR900359 analogs show no inhibition of other G protein subtypes except the Gq, G11 and G14 proteins. Here we report the rationalization of the high potency of FR900359 and efforts towards understanding the G protein subtype selectivity by synthesis of a collection of structurally and stereochemically diverse analogs of YM-254890 using an efficient synthetic protocol. We performed the first conformational study of YM-254890 in aqueous solution by NMR spectroscopy and replica exchange molecular dynamics, which suggested that the combined contribution of residues with appropriate size, stereochemistry and conformational stability are critical for inhibitory potency. Moreover, in addition to the fit of the binding pocket, more factors should be taken into consideration for the development of compounds targeting other G proteins.

U2 - 10.1016/j.ejmech.2018.07.023

DO - 10.1016/j.ejmech.2018.07.023

M3 - Journal article

C2 - 30055466

SN - 0223-5234

VL - 156

SP - 847

EP - 860

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

Structure–activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359

Abstract

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