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Galectin-8N-selective 4-halophenylphthalazinone-galactals double π stack in a unique pocketvan Klaveren, Sjors ...alectin-8 contains two different carbohydrate recognition domains (CRDs). Selective inhibitors for at least one CRD are desirable for galectin-8 biology studies and potentially for pharmacological ... purposes. Structure-guided design led to the discovery of potent and selective glycomimetic–heterocycle hybrid ligands, with a 4-(p-bromophenyl)phthalazinone derivative displaying a 34 μM Kd for galectin-8N (N-terminal CRD), no binding to galectin-8C (C-terminal CRD), -1, -3, -4N, -7, -9C, or -9N, and >40-fold selectivity over galectin-4C. Selectivity was achieved with the halogenated 4-phenylphthalazinone moiety occupying a galectin-8N-specific sub-pocket. A 1.30 Å resolution X-ray structure revealed the phthalazinone moiety stacking with Arg45 and the 4-bromophenyl moiety stacking both Arg59 and Tyr141 of galectin-8N. Physicochemical and in vitro ADME studies revealed a desirable LogD, which also translated to good passive permeability. The chemical, microsome, and plasma stability support these compounds as promising tool compounds and candidates for hit-to-lead optimization.Type of material - article, component part ; adult, seriousPublish date - 2024Language - englishCOBISS.SI-ID - 203686403
Author
van Klaveren, Sjors |
Hassan, Mujtaba |
Håkansson, Maria |
Johnsson, Richard E. |
Larsson, Jessica |
Jakopin, Žiga |
Anderluh, Marko |
Leffler, Hakon |
Tomašič, Tihomir |
Nilsson, Ulf, farmacevt
Topics
Farmacevtska kemija |
galectin-8 |
phthalazinone |
glycomimetic |
X-ray |
ADME |
carbohydrates |
crystal structure |
ligands |
selectivity |
stability |
ogljikovi hidrati |
kristalna struktura |
ligandi |
selektivnost |
stabilnost |
galektin-8 |
ftalazinon |
glikomimetično |
rentgensko slikanje |
ADME
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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van Klaveren, Sjors | |
Hassan, Mujtaba | |
Håkansson, Maria | |
Johnsson, Richard E. | |
Larsson, Jessica | |
Jakopin, Žiga | 26496 |
Anderluh, Marko | 21456 |
Leffler, Hakon | |
Tomašič, Tihomir | 28334 |
Nilsson, Ulf, farmacevt |
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