Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors
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Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors. / Voss, Jan H.; Crüsemann, Max; Bartling, Christian R.O.; Kehraus, Stefan; Inoue, Asuka; König, Gabriele M.; Strømgaard, Kristian; Müller, Christa E.
I: iScience, Bind 26, Nr. 4, 106492, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Structure-affinity and structure-residence time relationships of macrocyclic Gαq protein inhibitors
AU - Voss, Jan H.
AU - Crüsemann, Max
AU - Bartling, Christian R.O.
AU - Kehraus, Stefan
AU - Inoue, Asuka
AU - König, Gabriele M.
AU - Strømgaard, Kristian
AU - Müller, Christa E.
N1 - Funding Information: This study was supported with a research grant from the Deutsche Forschungsgemeinschaft ( FOR2372 ; MU1665/7-2 ), the Open Access Publication Fund of the University of Bonn , and the Bonn International Graduate School of Drug Sciences. A.I. was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI grants 21H04791 , 21H05113 and JPJSBP120213501, and the Japan Science and Technology Agency (JST) grant JPMJFR215T . Publisher Copyright: © 2023 The Authors
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Biochemistry
KW - Biological sciences
KW - Pharmacology
U2 - 10.1016/j.isci.2023.106492
DO - 10.1016/j.isci.2023.106492
M3 - Journal article
C2 - 37091255
AN - SCOPUS:85154024221
VL - 26
JO - iScience
JF - iScience
SN - 2589-0042
IS - 4
M1 - 106492
ER -
ID: 346408022