Structure-affinity and structure-residence time relationships of macrocyclic Gα_q protein inhibitors.

ABSTRACT: The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gα_q/11 proteins. They are important pharmacological tools and have potential as therapeutic drugs. The hydrogenated, tritium-labeled YM and FR derivatives display largely different residence times despite similar structures. In the present study we established a competition-association binding assay to determine the dissociation kinetics of unlabeled G_q protein inhibitors. Structure-affinity and structure-residence time relationships were analyzed. Small structural modifications had a large impact on residence time. YM and FR exhibited 4- to 10-fold higher residence times than their hydrogenated derivatives. While FR showed pseudo-irreversible binding, YM displayed much faster diss

SUBMITTER: Voss JH 

PROVIDER: S-EPMC10119753 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature