ACSL4

Long-chain-fatty-acid--CoA ligase 4

Score: 0.717 Price: $0.50 Low Druggability Status: active Wiki: ACSL4

HYPOTHESES

PAPERS

KG EDGES

357

DEBATES

3D Protein Structure

🧬 ACSL4 — PDB 4WB5 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.41

Clinical Stage

Phase III

Target Class

Enzyme

Safety

0.65

Druggability Analysis

Drug Development0.45

Structural Tractability0.30

Target Class0.85

Safety Profile0.65

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (4 compounds)

Therapeutic Areas:

Neuroinflammation Alzheimer's disease Parkinson's disease Neurodegeneration (amyotrophic lateral sclerosis, frontotemporal dementia) Ischemic stroke/neuronal injury Retinal degeneration Traumatic brain injury

Druggability Rationale: ACSL4 is tractable (0.72 druggability score) as a small-molecule target due to its well-characterized enzymatic active site and validation by existing PPAR-gamma agonists (rosiglitazone, troglitazone) demonstrating in vivo ACSL4 inhibition. The enzyme's role as a metabolic checkpoint in ferroptosis provides a clear mechanistic link to neuroprotection, particularly in neurodegenerative diseases driven by microglial ferroptosis.

Mechanism: Enzyme inhibition — blocking ACSL4 prevents incorporation of PUFAs into membrane phospholipids, reducing ferroptosis susceptibility

Drug Pipeline (4 compounds)

Known Drugs:

Triacsin C (Preclinical)

Rosiglitazone (Approved (diabetes))

Pioglitazone (Approved (diabetes))

PRGL493 (Preclinical)

Structural Data:

PDB —AlphaFold ✓Cryo-EM —

UniProt: O60488

Binding Pocket Analysis:

ACSL4 possesses a conserved adenylation domain that binds long-chain fatty acids (particularly arachidonic acid) and ATP/AMP as cofactors. The binding pocket accommodates C20 polyunsaturated fatty acids with high affinity, offering opportunities for selective small-molecule inhibitors that exploit ACSL4-specific substrate preferences and isoform-divergent residues around the fatty acid-binding cavity.

🧬 3D Protein Structure

🧬 ACSL4 — PDB 4WB5 Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

ACSL4 selectivity against the five human ACSL isoforms (ACSL1, 3, 5, 6) is achievable but requires optimization, as rosiglitazone's ACSL4 inhibition is an off-target effect of PPAR-gamma binding. Off-target liabilities include unintended PPAR pathway modulation and potential effects on other lipid metabolism enzymes; structure-based design is needed to decouple ACSL4 inhibition from PPAR engagement.