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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Discovery of inhibitory fragments that selectively target spire2-FMN2 interaction.
J. Med. Chem. 66, 15715-15727 (2023)
Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2-FMN2 but not the Spire1-FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an in-house library of 755 compounds and subsequently validated in multiple orthogonal biophysical assays, including fluorescence polarization, microscale thermophoresis, and 1H-15N HSQC nuclear magnetic resonance. Extensive structure-activity relationships combined with molecular docking followed by chemical optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chemical probes targeting the Spire2-FMN2 interaction.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Actin Nucleation; Protein; Domain; Spire
ISSN (print) / ISBN
0022-2623
e-ISSN
1520-4804
Zeitschrift
Journal of Medicinal Chemistry
Quellenangaben
Band: 66,
Heft: 23,
Seiten: 15715-15727
Verlag
American Chemical Society (ACS)
Verlagsort
1155 16th St, Nw, Washington, Dc 20036 Usa
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Structural Biology (STB)
Förderungen
European Union in the framework of the Smart Growth Operational Programme, Measure 4.2
National Science Centre, Poland
PRELUDIUM 14 grant
Narodowe Centrum Nauki
National Science Centre, Poland
PRELUDIUM 14 grant
Narodowe Centrum Nauki