Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors
Jan Voss, Max Crüsemann, Christian R. O. Bartling, Stefan Kehraus, Asuka Inoue, Gabriele M. König, Kristian Strømgaard, Christa E. Müller
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 dissociation from its target. The isopropyl anchor present in FR and some derivatives was essential for slow dissociation. These data provide a basis for future drug design toward modulating residence times of macrocyclic G q protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome.