CRH

Corticotropin Releasing Hormone

Score: 0.538 Price: $0.54 Low Druggability Status: active Wiki: CRH

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

281

DEBATES

3D Protein Structure

🧬 CRH — PDB 4Z9R Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.34

Clinical Stage

Approved

Target Class

Ligand

Safety

0.60

Druggability Analysis

Drug Development0.60

Structural Tractability0.70

Target Class0.50

Safety Profile0.60

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (1 compounds)

Therapeutic Areas:

Major depressive disorder Anxiety disorders Post-traumatic stress disorder (PTSD) Chronic stress-related neurodegeneration Cognitive decline and dementia Neuroinflammation HPA axis-mediated disorders

Druggability Rationale: CRH (Corticotropin-Releasing Hormone) represents a challenging but promising neurotherapeutic target with low druggability, primarily due to its complex stress-response signaling mechanism. While antalarmin demonstrates initial proof-of-concept as a CRH receptor antagonist, the limited structural data and complex receptor dynamics suggest significant medicinal chemistry optimization would be required to develop clinically effective neurodegeneration therapeutics. The presence of AlphaFold structural predictions and multiple PDB structures provides a computational foundation for rational drug design, though translating these insights into selective, blood-brain barrier-penetrant small molecules remains a substantial scientific challenge.

Mechanism: CRH receptor antagonist blocking stress hormone signaling

Drug Pipeline (1 compounds)

Known Drugs:

Antalarmin (clinical_trial) — stress-related disorders

Structural Data:

PDB (4) ✓AlphaFold ✓Cryo-EM ✓

1ZVV 2AK7 2RLZ 3EHU

UniProt: P06850

Binding Pocket Analysis:

The CRH-R1 receptor contains an extracellular ligand-binding domain characteristic of class B GPCRs, with multiple high-resolution structures revealing a shallow peptide-recognition surface rather than a classic deep pocket; known antagonists like Antalarmin occupy an allosteric or partially-overlapping site distinct from the native CRH N-terminal binding region.

🧬 3D Protein Structure

🧬 CRH — PDB 4Z9R Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

Selectivity is a primary concern due to CRH receptor subtypes (CRH-R1 and CRH-R2) with distinct CNS and peripheral roles; selective CRH-R1 antagonism is preferred to avoid compensatory peripheral stress responses. Off-target GPCR cross-reactivity represents a significant risk, requiring careful structure-activity relationship optimization.