COX4I1

Cytochrome C Oxidase Subunit 4I1

Score: 0.543 Price: $0.54 Low Druggability Status: active Wiki: COX4I1

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

152

DEBATES

3D Protein Structure

🧬 COX4I1 — PDB 2DYR Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.42

Clinical Stage

Phase II

Target Class

Enzyme

Safety

0.20

Druggability Analysis

Drug Development0.65

Structural Tractability0.70

Target Class0.85

Safety Profile0.20

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (4 compounds)

2 Approved · 1 Preclinical

Therapeutic Areas:

Primary mitochondrial myopathy Heart failure and cardiomyopathy Leber hereditary optic neuropathy Neurodegenerative diseases (Parkinson's, Alzheimer's) Statin-induced myopathy Ischemia-reperfusion injury Age-related mitochondrial dysfunction

Druggability Rationale: COX4I1 demonstrates medium druggability (0.55) due to its well-characterized structural features (5 PDB structures, cryo-EM data, 3.6 Å resolution) and proven clinical validation through approved agents like Idebenone and CoQ10. However, direct enzymatic targeting is challenging because COX4I1 is a regulatory rather than catalytic subunit, necessitating indirect approaches that modulate electron transport efficiency or stabilize complex IV assembly rather than occupying a classical active site.

Mechanism: Drugs targeting COX4I1 pathway would enhance electron transport chain efficiency or stabilize complex IV assembly, improving ATP production and reducing oxidative stress in mitochondria. These agents work by either promoting mitochondrial bioenergetics, acting as electron donors/acceptors, or preventing complex IV degradation in diseases with impaired oxidative phosphorylation.

Drug Pipeline (4 compounds)

2 Approved · 1 Preclinical

Known Drugs:

Elamipretide (MTP131) (phase3) — Primary mitochondrial myopathy and heart failure

Idebenone (approved) — Leber hereditary optic neuropathy

Coenzyme Q10 (Ubiquinone) (approved) — Mitochondrial disease and statin-induced myopathy

SS-31 (Szeto-Schiller peptide 31) (preclinical) — Mitochondrial dysfunction and oxidative stress

Structural Data:

PDB (5) ✓AlphaFold ✓Cryo-EM ✓

7COH 8H8R 8H8S 9A1K 9W2Z

UniProt: H3BN72

Binding Pocket Analysis:

COX4I1 lacks a traditional druggable active site as a regulatory subunit; instead, binding pockets exist at protein-protein interaction interfaces (COX1/COX2/COX3 integration sites) and potential allosteric sites for stabilizing complex IV assembly. Existing drugs primarily work as electron donors/shuttles (CoQ10, Idebenone) or cardiolipin-targeting peptides (Elamipretide) rather than occupying discrete binding pockets.

🧬 3D Protein Structure

🧬 COX4I1 — PDB 2DYR Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

Selectivity challenges include potential off-target effects on other electron transport chain complexes and difficulty distinguishing between COX4I1 and its isoform COX4I2, which share high sequence homology. The mitochondrial compartmentalization of this target provides a selectivity advantage by limiting systemic exposure, though this also complicates drug delivery and bioavailability.