Back to Search
Start Over
Structure-activity relationship and conformational studies of the natural product cyclic depsipeptides YM-254890 and FR900359.
- 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.)
- Subjects :
- Amino Acid Sequence
Animals
Binding Sites drug effects
CHO Cells
Cricetulus
Crystallography, X-Ray
GTP-Binding Protein alpha Subunits, Gq-G11 chemistry
GTP-Binding Protein alpha Subunits, Gq-G11 metabolism
Models, Molecular
Protein Conformation
Structure-Activity Relationship
Depsipeptides chemistry
Depsipeptides pharmacology
GTP-Binding Protein alpha Subunits, Gq-G11 antagonists & inhibitors
Peptides, Cyclic chemistry
Peptides, Cyclic pharmacology
Subjects
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