Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors
Jan H. Voss,
Max Crüsemann,
Christian R.O. Bartling,
Stefan Kehraus,
Asuka Inoue,
Gabriele M. König,
Kristian Strømgaard,
Christa E. Müller
Affiliations
Jan H. Voss
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany
Max Crüsemann
Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany
Christian R.O. Bartling
Department of Drug Design and Pharmacology, Center for Biopharmaceuticals, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Stefan Kehraus
Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany
Asuka Inoue
Tohoku University, Graduate School of Pharmaceutical Sciences, Sendai, Miyagi 980-8578, Japan
Gabriele M. König
Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany
Kristian Strømgaard
Department of Drug Design and Pharmacology, Center for Biopharmaceuticals, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Christa E. Müller
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany; Corresponding author
Summary: The macrocyclic depsipeptides YM-254890 (YM) and FR900359 (FR) are potent inhibitors of Gαq/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 Gq 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 Gq protein inhibitors, which has been recognized as a crucial determinant for therapeutic outcome.
