HCRTR2

Hypocretin Receptor 2

Score: 0.655 Price: $0.65 Medium Druggability Status: active Wiki: HCRTR2

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

DEBATES

3D Protein Structure

🧬 HCRTR2 — PDB 7LS3 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 Alzheimer's disease (circadian dysfunction) Neurodegenerative diseases with sleep disturbances Lewy body dementia Parkinson's disease (sleep complications) Narcolepsy (paradoxical indication) Age-related sleep fragmentation

Druggability Rationale: HCRTR2 exhibits exceptional druggability due to its well-characterized GPCR architecture, high-resolution crystal structures (1.96 Å), and validated clinical precedent with approved antagonists (Suvorexant, Lemborexant). The target's 0.90 druggability score reflects established ligand-binding capabilities and amenability to small-molecule optimization, with extensive structural biology support including 11 PDB structures and AlphaFold/cryo-EM data.

Mechanism: Small molecule antagonist blocking orexin receptor signaling

Drug Pipeline (2 compounds)

Known Drugs:

Suvorexant (Approved) — Insomnia

Lemborexant (Approved) — Insomnia

Structural Data:

PDB (11) ✓AlphaFold ✓Cryo-EM ✓

4S0V 5WQC 5WS3 6TPG 6TPJ+6 more

UniProt: S4WX84

Binding Pocket Analysis:

HCRTR2 contains a well-defined orthosteric binding pocket within the transmembrane helical bundle, characterized by aromatic residues and polar contact points that accommodate both lipophilic and hydrogen-bonding pharmacophores, as revealed by multiple high-resolution structures enabling structure-based drug design and structure-activity relationship studies.

🧬 3D Protein Structure

🧬 HCRTR2 — PDB 7LS3 Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

Selectivity between OX1R and OX2R isoforms is clinically relevant, as HCRTR2-selective antagonism may provide superior tolerability profiles compared to dual antagonists; however, cross-reactivity with related GPCRs and potential CNS off-target effects (e.g., monoamine receptors) require careful pharmacological profiling during lead optimization.