4-Dimethylaminophenol: A 'Smaller'-Molecule PPI Inhibitor Targeting the PSD95 GK Domain Against Ischemic Stroke.

Area of Science:

• Neuroscience
• Pharmacology
• Structural Biology

Background:

• Protein-protein interactions (PPIs) are crucial in cellular processes but challenging therapeutic targets.
• Postsynaptic density protein 95 (PSD95) plays a key role in synaptic function and is implicated in neurological disorders.
• The Guanylate Kinase-like (GK) domain of PSD95 is a potential target for modulating its interactions.

Purpose of the Study:

• To identify novel inhibitors of PPIs targeting the PSD95 GK domain.
• To investigate the neuroprotective effects of identified inhibitors.
• To explore the potential of small molecules as PPI inhibitors for neurological diseases.

Main Methods:

• Fragment-based drug discovery.
• X-ray crystallography to confirm direct binding.
• In vitro and in vivo assays to evaluate neuroprotection and inhibition of PSD95/nNOS interaction.
• Structure-activity relationship (SAR) studies.

Main Results:

• 4-dimethylaminophenol, a small molecule, was identified as a novel inhibitor of the PSD95 GK domain.
• Direct binding of 4-dimethylaminophenol to PSD95 GK was confirmed structurally.
• A previously unknown PDZ-independent interaction between PSD95 GK and nNOS was discovered and inhibited by the compound.
• The compound demonstrated neuroprotective effects by reducing nitric oxide overproduction and excitotoxicity in vitro and in vivo.
• SAR studies identified key functional groups and potential for enhanced binding through halogen substitution.

Conclusions:

• 4-dimethylaminophenol is a promising neuroprotective lead compound for ischemic stroke, leveraging its BBB permeability and established safety profile.
• Small molecules targeting PPIs, particularly the PSD95/nNOS interaction, offer a viable therapeutic strategy.
• This study highlights the potential of ultralow molecular weight compounds as effective PPI inhibitors.