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

doi:10.1016/j.isci.2023.106492

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

iScience. 2023 Mar 23;26(4):106492. doi: 10.1016/j.isci.2023.106492. eCollection 2023 Apr 21.

Authors

Jan H Voss¹, Max Crüsemann², Christian R O Bartling³, Stefan Kehraus², Asuka Inoue⁴, Gabriele M König², Kristian Strømgaard³, Christa E Müller¹

Affiliations

¹ PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
² Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
³ Department of Drug Design and Pharmacology, Center for Biopharmaceuticals, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
⁴ Tohoku University, Graduate School of Pharmaceutical Sciences, Sendai, Miyagi 980-8578, Japan.

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.

Keywords: Biochemistry; Biological sciences; Pharmacology.