CERS2

Ceramide synthase 2

Score: 0.520 Price: $0.52 Low Druggability Status: active Wiki: CERS2

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

DEBATES

3D Protein Structure

🧬 CERS2 — PDB 5YSR Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.28

Clinical Stage

Phase II

Target Class

Enzyme

Safety

0.40

Druggability Analysis

Drug Development0.30

Structural Tractability0.30

Target Class0.85

Safety Profile0.40

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (1 compounds)

Therapeutic Areas:

Alzheimer's disease Neurodegeneration Parkinson's disease Amyotrophic lateral sclerosis (ALS) Sphingolipid metabolism disorders Neuroinflammation Neuroprotection

Druggability Rationale: CERS2 has low druggability (0.30) despite being an enzyme with an established active site, primarily due to the lack of available crystal structures (0 PDB entries) and the mycotoxin nature of the only known inhibitor (Fumonisin B1), which raises safety concerns for clinical translation. However, the AlphaFold model availability and validation in Phase 2 clinical trials suggest that structure-based drug design approaches may still yield selective, non-toxic inhibitors with improved pharmacological properties.

Mechanism: CERS2 inhibitors would reduce the enzymatic synthesis of very long-chain ceramides by blocking the condensation of serine and palmitoyl-CoA, thereby decreasing ceramide-mediated neuroinflammation and apoptosis implicated in neurodegenerative pathology. This modulation of the ceramide signaling cascade may provide neuroprotective effects in Alzheimer's disease and related neurodegenerative conditions.

Drug Pipeline (1 compounds)

Known Drugs:

Fumonisin B1 (research) — Ceramide synthase inhibitor (tool compound, mycotoxin)

Structural Data:

PDB —AlphaFold ✓Cryo-EM —

UniProt: H0YNU7

Binding Pocket Analysis:

Structural characterization is limited by the absence of experimental crystal structures; however, the AlphaFold model enables computational prediction of the catalytic pocket where serine and palmitoyl-CoA condensation occurs. Based on ceramide synthase homologs, the active site likely contains conserved motifs for CoA-thioester binding and a serine-binding pocket, though direct experimental validation through X-ray crystallography or cryo-EM is needed to guide rational inhibitor design.

🧬 3D Protein Structure

🧬 CERS2 — PDB 5YSR Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

CERS2 selectivity against other ceramide synthase isoforms (CERS1, CERS3–CERS6) is critical, as off-target inhibition could disrupt ceramide homeostasis and cause unintended lipid metabolism alterations in non-neuronal tissues. The substrate specificity for very long-chain (C22–C26) fatty acids may provide a degree of isoform selectivity, but comprehensive kinetic profiling will be essential.