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

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. [Display omitted] •5 analogs were designed and synthesized to rationalize the high potency of FR900359.•2 compounds were prepared to understand the subtype biased G protein inhibition.•The first conformational study of YM-254890 was explored.•The conformational stability of depsipeptides is crucial for potent Gq inhibition.•The fit of binding pocket was not sufficient for Gs selective inhibitors discovery.