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

Authors :
Zhang H
Nielsen AL
Boesgaard MW
Harpsøe K
Daly NL
Xiong XF
Underwood CR
Haugaard-Kedström LM
Bräuner-Osborne H
Gloriam DE
Strømgaard K
Source :
European journal of medicinal chemistry [Eur J Med Chem] 2018 Aug 05; Vol. 156, pp. 847-860. Date of Electronic Publication: 2018 Jul 12.
Publication Year :
2018

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 G <subscript>q</subscript> protein subfamily. So far, all reported YM-254890 and FR900359 analogs show no inhibition of other G protein subtypes except the G <subscript>q</subscript> , G <subscript>11</subscript> and G <subscript>14</subscript> 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.<br /> (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Details

Language :
English
ISSN :
1768-3254
Volume :
156
Database :
MEDLINE
Journal :
European journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
30055466
Full Text :
https://doi.org/10.1016/j.ejmech.2018.07.023