HCRTR1

Hypocretin Receptor 1

Score: 0.662 Price: $0.66 Medium Druggability Status: active Wiki: HCRTR1

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

DEBATES

3D Protein Structure

🧬 HCRTR1 — PDB 4ZJ8 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.60

Clinical Stage

Approved

Target Class

Gpcr

Safety

0.70

Druggability Analysis

Drug Development0.60

Structural Tractability0.85

Target Class0.85

Safety Profile0.70

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (2 compounds)

Therapeutic Areas:

Insomnia and sleep disorders Narcolepsy Parkinson's disease (sleep disturbances) Alzheimer's disease (sleep-wake cycle disruption) Lewy body dementia REM sleep behavior disorder Restless leg syndrome

Druggability Rationale: HCRTR1 is highly druggable due to its well-validated GPCR scaffold, extensive structural characterization (14 PDB structures with 2.11 Å resolution), and proven clinical precedent with two approved antagonists (Suvorexant, Lemborexant) demonstrating efficacy and safety. The high druggability score (0.90) reflects a defined orthosteric binding pocket amenable to small molecule optimization and favorable pharmacological tractability.

Mechanism: Small molecule antagonist blocking orexin receptor signaling

Drug Pipeline (2 compounds)

Known Drugs:

Suvorexant (Approved) — Insomnia

Lemborexant (Approved) — Insomnia

Structural Data:

PDB (14) ✓AlphaFold ✓Cryo-EM —

4ZJ8 4ZJC 6TO7 6TOD 6TOS+9 more

UniProt: A6NMV7

Binding Pocket Analysis:

Structural data reveals a well-defined orthosteric binding pocket within the transmembrane helical bundle typical of GPCRs, with multiple allosteric modulation sites identified across the 14 available crystal structures. The 2.11 Å resolution structures (PDB: 4ZJ8, 4ZJC, 6TO7, 6TOD, 6TOS) enable high-resolution mapping of ligand-receptor interactions and structure-based drug design optimization.

🧬 3D Protein Structure

🧬 HCRTR1 — PDB 4ZJ8 Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

HCRTR1 selectivity versus HCRTR2 is critical to minimize potential off-target effects on appetite regulation and metabolic homeostasis; approved drugs like Suvorexant show dual antagonism, but isoform-selective agents are under investigation. Cross-reactivity with other GPCRs remains a consideration, though the orexin receptor family's distinct ligand binding profile provides inherent selectivity advantages.