CYP46A1

Cytochrome P450 Family 46 Subfamily A Member 1

Score: 0.572 Price: $0.57 Medium Druggability Status: active Wiki: CYP46A1

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

DEBATES

3D Protein Structure

🧬 CYP46A1 — PDB 2Q9F Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.51

Clinical Stage

Approved

Target Class

Enzyme

Safety

0.70

Druggability Analysis

Drug Development0.75

Structural Tractability0.85

Target Class0.85

Safety Profile0.70

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (1 compounds)

1 Approved

Therapeutic Areas:

Alzheimer's disease Neurodegeneration Cognitive decline Brain cholesterol metabolism disorders Neurodegenerative diseases with lipid dysmetabolism

Druggability Rationale: CYP46A1 is highly druggable (0.80 score) due to its well-defined active site architecture, extensive structural data (21 PDB structures at 1.4Å resolution), and proven chemical tractability demonstrated by Efavirenz's ability to modulate the enzyme. The enzyme's role as a rate-limiting metabolic checkpoint with clear biochemical output (24-hydroxycholesterol) provides excellent pharmacodynamic readouts for therapeutic efficacy.

Mechanism: Small molecule activator of cholesterol 24-hydroxylase enhancing brain cholesterol turnover

Drug Pipeline (1 compounds)

1 Approved

Known Drugs:

Efavirenz (approved) — HIV (repurposed for cholesterol metabolism)

Structural Data:

PDB (21) ✓AlphaFold ✓Cryo-EM —

2Q9F 2Q9G 3MDM 3MDR 3MDT+16 more

UniProt: G3V366

Binding Pocket Analysis:

The substrate-binding pocket accommodates cholesterol's rigid steroid ring system with high-resolution structural data revealing heme coordination and substrate positioning residues critical for regioselectivity. Allosteric activation sites distinct from the catalytic pocket may offer opportunities for selective activators with reduced off-target CYP450 effects.

🧬 3D Protein Structure

🧬 CYP46A1 — PDB 2Q9F Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

CYP46A1 selectivity is advantageous as the enzyme is predominantly brain-expressed and functionally unique in catalyzing cholesterol 24-hydroxylation, minimizing off-target cytochrome P450 interactions. However, modulators must avoid inhibiting other hepatic CYP450 isoforms, particularly given the repurposed use of Efavirenz, which carries known drug-drug interaction liabilities.