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

Zhang, Hang, Nielsen, Alexander L., Boesgaard, Michael W., Harpsøe, Kasper, Daly, Norelle L., Xiong, Xiao-Feng, Underwood, Christina R., Haugaard-Kedström, Linda M., Bräuner-Osborne, Hans, Gloriam, David E., and Strømgaard, Kristian (2018) Structure-activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359. European Journal of Medicinal Chemistry, 156. pp. 847-860.

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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(q) protein subfamily. So far, all reported YM-254890 and FR900359 analogs show no inhibition of other G protein subtypes except the G(q), G(11) and G(14) 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.

Item ID: 55618
Item Type: Article (Research - C1)
ISSN: 1768-3254
Keywords: G proteins, cyclic depsipeptides, SAR studies
Copyright Information: © 2018 Elsevier Masson SAS. All rights reserved.
Funders: Australian Research Council (ARC), European Research Council (ERC), Lundbeck Foundation (LF)
Projects and Grants: ARC LE160100218, ERC DE-ORPHAN 639125, LF R163-2013-16327
Date Deposited: 19 Sep 2018 09:00
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics) @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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