GJA1

Gap junction alpha-1 protein (Connexin 43)

Score: 0.578 Price: $0.58 Low Druggability Status: active Wiki: GJA1

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

167

DEBATES

3D Protein Structure

🧬 GJA1 — PDB 2ZW3 Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.36

Clinical Stage

Phase II

Target Class

Ion Channel

Safety

0.50

Druggability Analysis

Drug Development0.30

Structural Tractability0.85

Target Class0.85

Safety Profile0.50

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (1 compounds)

1 Preclinical

Therapeutic Areas:

Neurodegeneration (Alzheimer's disease, Parkinson's disease) Neuroinflammation Stroke/Ischemic injury Traumatic brain injury Gliosis modulation Cardiac arrhythmias Wound healing

Druggability Rationale: GJA1 demonstrates medium druggability (0.55) supported by extensive structural data (19 PDB structures, cryo-EM, AlphaFold models at 2.26 Å resolution) and the existence of tool compounds like carbenoxolone, which has advanced to clinical trials. However, the channel's role in ubiquitous cell-cell communication and essential cellular functions limits the therapeutic window, complicating the path to selective modulation without disrupting normal gap junction signaling.

Mechanism: Small molecule modulator of gap junction channel activity

Drug Pipeline (1 compounds)

1 Preclinical

Known Drugs:

Carbenoxolone (investigational) — Gap junction modulation

Structural Data:

PDB (19) ✓AlphaFold ✓Cryo-EM ✓

2N8T 3CYY 7F92 7F93 7F94+14 more

UniProt: P17302

Binding Pocket Analysis:

The transmembrane domains of connexin 43 form the channel pore and represent the primary binding site for small molecule modulators; carbenoxolone and related compounds likely target allosteric sites on the extracellular loops or transmembrane regions that regulate channel gating, based on structural analysis of the available PDB complexes and cryo-EM data.

🧬 3D Protein Structure

🧬 GJA1 — PDB 2ZW3 Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

Major selectivity challenge stems from GJA1's ubiquitous expression across tissues (neuronal, cardiac, vascular); off-target effects on other connexin isoforms (GJB1, GJC1) and unintended systemic gap junction disruption are significant risks. Tissue-specific modulation and isoform selectivity represent key differentiators for improved therapeutic safety.