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Discovery of Inhibitory Fragments That Selectively Target Spire2-FMN2 Interaction.

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.

SUBMITTER: Kitel R

PROVIDER: S-EPMC10726347 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Discovery of Inhibitory Fragments That Selectively Target Spire2-FMN2 Interaction.

Kitel Radoslaw R Surmiak Ewa E Borggräfe Jan J Kalinowska-Tluscik Justyna J Golik Przemyslaw P Czub Miroslawa M Uzar Wiktor W Musielak Bogdan B Madej Mariusz M Popowicz Grzegorz M GM Dubin Grzegorz G Holak Tad A TA

Journal of medicinal chemistry 20231201 23

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 ...[more]

PMID: 38039505

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