TY - JOUR

T1 - Identification of novel fragments binding to the PDZ1-2 domain of PSD-95

AU - Zang, Jie

AU - Ye, Fei

AU - Solbak, Sara

AU - Høj, Lars Jakobsen

AU - Zhang, Mingjie

AU - Bach, Anders

N1 - © 2020 Wiley-VCH GmbH.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1002/cmdc.202000865

DO - 10.1002/cmdc.202000865

M3 - Journal article

C2 - 33305877

VL - 16

SP - 949

EP - 954

JO - Farmaco

JF - Farmaco

SN - 1860-7179

IS - 6

ER -