Discovery of Inhibitory Fragments That Selectively Target Spire2-FMN2 Interaction.
J Med Chem
; 66(23): 15715-15727, 2023 12 14.
Article
em En
| MEDLINE
| ID: mdl-38039505
ABSTRACT
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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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Descoberta de Drogas
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2023
Tipo de documento:
Article