Identification of novel fragments binding to the PDZ1-2 domain of PSD-95
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
Originalsprog | Engelsk |
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Tidsskrift | ChemMedChem |
Vol/bind | 16 |
Udgave nummer | 6 |
Sider (fra-til) | 949-954 |
ISSN | 1860-7179 |
DOI | |
Status | Udgivet - 2021 |
ID: 252945421