PLA2G6

Phospholipase A2 group VI

Score: 0.535 Price: $0.54 Low Druggability Status: active Wiki: PLA2G6

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

DEBATES

3D Protein Structure

🧬 PLA2G6 — PDB 2N3W Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.36

Clinical Stage

Approved

Target Class

Enzyme

Safety

0.30

Druggability Analysis

Drug Development0.75

Structural Tractability0.30

Target Class0.85

Safety Profile0.30

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (2 compounds)

1 Approved

Therapeutic Areas:

Neurodegeneration with brain iron accumulation (NBIA) Neurodegenerative diseases Neuroinflammation Oxidative stress-related neurological disorders Membrane stability disorders Neuropsychiatric conditions (secondary to PLA2G6 dysfunction)

Druggability Rationale: PLA2G6 presents medium druggability (0.60) due to its well-defined enzyme class with a catalytic active site amenable to small molecule inhibition, supported by existing approved drugs (desipramine) and research tool compounds (bromoenol lactone) with demonstrated iPLA2 inhibitory activity. However, the lack of experimental structural data (no PDB entries, no cryo-EM) and reliance solely on AlphaFold predictions limit confidence in rational drug design, though the calcium-independent mechanism offers a distinct biochemical handle for inhibition.

Mechanism: Small molecule inhibitor of calcium-independent phospholipase A2 activity

Drug Pipeline (2 compounds)

1 Approved

Known Drugs:

Desipramine (approved) — Tricyclic antidepressant with iPLA2 inhibitory activity

Bromoenol lactone (research) — Selective iPLA2 inhibitor (tool compound)

Structural Data:

PDB —AlphaFold ✓Cryo-EM —

UniProt: A0A590UJC7

Binding Pocket Analysis:

The active site architecture remains undefined experimentally, but as a calcium-independent phospholipase, PLA2G6 likely contains a serine/aspartate catalytic dyad typical of lipase enzymes with substrate binding pockets accommodating fatty acyl chains; AlphaFold predictions may suggest potential allosteric or membrane-interaction surfaces, but experimental validation through mutagenesis or crystallography is needed to confirm inhibitor binding modes.

🧬 3D Protein Structure

🧬 PLA2G6 — PDB 2N3W Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

A major selectivity challenge is distinguishing PLA2G6 inhibition from other phospholipase A2 isoforms (PLA2G4, PLA2G5, etc.), as structural similarity across the family is high; selectivity will require detailed kinetic profiling and target engagement studies. Off-target liabilities with existing inhibitors like desipramine (tricyclic antidepressant with broad pharmacology) highlight the need for PLA2G6-selective scaffolds to avoid unintended neurological effects.