GABRA1

Gamma-aminobutyric acid receptor subunit alpha-1

Score: 0.718 Price: $0.72 High Druggability Status: active Wiki: GABRA1

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

119

DEBATES

3D Protein Structure

🧬 GABRA1 — PDB 6D6U Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

High

Score: 0.90

Clinical Stage

Approved

Target Class

Ion Channel

Safety

0.60

Druggability Analysis

Drug Development1.00

Structural Tractability0.95

Target Class0.85

Safety Profile0.60

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (4 compounds)

3 Approved · 1 Phase III

Therapeutic Areas:

Anxiety disorders Seizure disorders/Epilepsy Insomnia Alcohol withdrawal Neurodegenerative diseases (Alzheimer's, Parkinson's) Neuroinflammation Status epilepticus Muscle spasticity

Druggability Rationale: GABRA1 encodes the α1 subunit of GABA-A receptors, which demonstrates high druggability evidenced by multiple approved benzodiazepine compounds and extensive structural data across 79 PDB entries. The target's existing positive allosteric modulation mechanism and well-characterized AlphaFold structural prediction (with best resolution of 2.4Å) suggest significant potential for targeted neurological intervention, particularly for disorders involving GABAergic signaling dysregulation.

Mechanism: GABRA1 mediates inhibitory neurotransmission through GABA-A receptor subunit composition, modulating neuronal excitability and synaptic signaling. In neurodegeneration contexts, alterations in GABRA1 expression or function can contribute to neuronal hyperexcitability, oxidative stress, and potentially accelerated cellular damage mechanisms associated with progressive neurological disorders.

Drug Pipeline (4 compounds)

3 Approved · 1 Phase III

Known Drugs:

Diazepam (approved) — Anxiety, seizures

Lorazepam (approved) — Anxiety, seizures

Midazolam (approved) — Sedation, anesthesia

CHEMBL262075 (phase_3)

Structural Data:

PDB (79) ✓AlphaFold ✓Cryo-EM ✓

5OSA 5OSB 5OSC 6CDU 6D1S+74 more

UniProt: P14867

Binding Pocket Analysis:

The benzodiazepine binding site is located at the interface between α and γ subunits in the extracellular domain, with allosteric modulation mediated through conformational changes. Structural data reveals a highly conserved pocket accommodating diverse scaffolds, enabling rational design of subtype-selective ligands with improved safety profiles.

🧬 3D Protein Structure

🧬 GABRA1 — PDB 6D6U Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

GABRA1 selectivity is challenging due to high sequence homology across GABA-A receptor subunits (α1-α6), leading to off-target effects and safety concerns with CNS penetration. Isoform-selective modulation remains therapeutically desirable to reduce sedation, cognitive impairment, and abuse potential while maintaining efficacy.