VCP

Valosin containing protein

Score: 0.590 Price: $0.59 Medium Druggability Status: active Wiki: VCP

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

345

DEBATES

3D Protein Structure

🧬 VCP — PDB 5FTK Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.50

Clinical Stage

Phase I

Target Class

Enzyme

Safety

0.30

Druggability Analysis

Drug Development0.20

Structural Tractability0.95

Target Class0.85

Safety Profile0.30

Key Metrics

PDB Structures:

130

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (1 compounds)

Therapeutic Areas:

Neurodegenerative diseases (inclusion body myopathy with frontotemporal dementia) Protein aggregation disorders (Alzheimer's, Parkinson's, ALS) Cancer (proteasomal dysfunction and ERAD inhibition) Autophagy-related disorders ER-associated protein degradation (ERAD) dysfunction

Druggability Rationale: VCP is highly druggable (0.75 score) due to its well-characterized ATPase active site, extensive structural data (130+ PDB entries at 1.55 Å resolution), and proven precedent with CB-5083 advancing to clinical trials. The enzyme's defined nucleotide-binding pocket and accessibility to small-molecule inhibitors make it an excellent target for competitive ATP-site binders affecting protein quality control pathways.

Mechanism: Small molecule inhibitors of VCP ATPase activity affecting protein quality control

Drug Pipeline (1 compounds)

Known Drugs:

CB-5083 (phase1) — Cancer (neurodegenerative applications explored)

Structural Data:

PDB (130) ✓AlphaFold ✓Cryo-EM ✓

10QQ 10QR 1R7R 1S3S 3CF0+125 more

UniProt: A0A7P0T8A3

Binding Pocket Analysis:

VCP possesses two tandem AAA+ ATPase domains (D1 and D2) with distinct nucleotide-binding sites; CB-5083 and related inhibitors primarily target the D2 domain ATP-binding pocket, which offers favorable geometry for selective small-molecule occupancy. The D1 and D2 interface also presents an allosteric pocket exploitable for mechanism-based selectivity and modulation of ATP hydrolysis kinetics without competing directly with abundant cellular ATP.

🧬 3D Protein Structure

🧬 VCP — PDB 5FTK Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

VCP selectivity is moderately challenging due to AAA+ ATPase family homology (p97/VCP orthologs, NSF, other AAA-ATPases), requiring structural selectivity through the D1/D2 domain architecture or allosteric modulation to minimize off-target effects on related ATPases. Isoform selectivity is less of a concern as VCP lacks major splice variants, but tissue distribution and functional context differences necessitate careful pharmacodynamic assessment.