GPX4

Glutathione peroxidase 4

Score: 0.593 Price: $0.59 Low Druggability Status: active Wiki: GPX4

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

1173

DEBATES

3D Protein Structure

🧬 GPX4 — PDB 2OBI Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.41

Clinical Stage

Phase II

Target Class

Enzyme

Safety

0.30

Druggability Analysis

Drug Development0.30

Structural Tractability0.85

Target Class0.85

Safety Profile0.30

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (2 compounds)

2 Preclinical

Therapeutic Areas:

Neurodegeneration (Parkinson's disease, Alzheimer's disease, ALS) Stroke/ischemic injury Traumatic brain injury Ferroptosis-dependent cancers (oncology) Spinal cord injury

Druggability Rationale: GPX4 demonstrates medium druggability (0.55) with clear structural tractability evidenced by 24 PDB structures at 1.01 Å resolution and active investigation of tool compounds (RSL3, ML210). However, the target's essential cytoprotective function against ferroptosis presents a double-edged challenge: inhibitors show cancer research potential but carry high neurotoxicity risk, while activators require overcoming the enzyme's already-efficient catalytic mechanism and potential off-target effects on related peroxidases.

Mechanism: Small molecule inhibitor or activator of peroxidase activity

Drug Pipeline (2 compounds)

2 Preclinical

Known Drugs:

RSL3 (investigational) — Cancer research tool

ML210 (investigational) — Research tool compound

Structural Data:

PDB (24) ✓AlphaFold ✓Cryo-EM —

2GS3 2OBI 5H5Q 5H5R 5H5S+19 more

UniProt: P36969

Binding Pocket Analysis:

The active site features a selenocysteine residue (Sec47 in human GPX4) coordinated by structural cysteines, creating a highly specialized catalytic pocket optimized for lipid hydroperoxide reduction; structural data suggests potential allosteric modulation sites distinct from the active site that could enable selective activation without direct active site competition with physiological substrates.

🧬 3D Protein Structure

🧬 GPX4 — PDB 2OBI Click to expand interactive 3D viewer

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

Selectivity & Safety Considerations

GPX4 selectivity is complicated by structural similarity to other glutathione peroxidases (GPX1-GPX3, GPX5-GPX8), requiring careful ligand design to avoid off-target peroxidase inhibition that could dysregulate redox homeostasis. Tissue-specific expression patterns (particularly high in nervous system and testis) may enable some selectivity advantage through pharmacokinetics, but active site conservation poses inherent selectivity challenges.