Identification of novel fragments binding to the PDZ1-2 domain of PSD-95

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Inhibition of PSD-95 has emerged as a promising strategy for treatment of ischemic stroke as shown with peptide-based compounds that target the PDZ domains of PSD-95. In contrast, developing potent and drug-like small-molecules against the PSD-95 PDZ domains has so far been unsuccessful. Here, we explore the druggability of the PSD-95 PDZ1-2 domain and use fragment screening to investigate if this protein is prone to bind small-molecules. We screened 2,500 fragments by fluorescence polarization (FP) and validated the hits by surface plasmon resonance (SPR) including an inhibition counter-test and found four promising fragments. Three ligand-efficient fragments were shown by 1H-15N HSQC NMR to bind in the small hydrophobic P0 pockets of PDZ1-2, and one of them underwent structure-activity relationship (SAR) studies. Overall, we demonstrate that fragment screening can successfully be applied to PDZ1-2 of PSD-95 and disclose novel fragments that can serve as starting points for optimization towards small-molecule PDZ domain inhibitors.

Original languageEnglish
JournalChemMedChem
Volume16
Issue number6
Pages (from-to)949-954
ISSN1860-7179
DOIs
Publication statusPublished - 2021

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