TLR4

Toll-like receptor 4

Score: 0.660 Price: $0.66 Low Druggability Status: active Wiki: TLR4

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

1139

DEBATES

3D Protein Structure

🧬 TLR4 — PDB 3ULB Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Low

Score: 0.41

Clinical Stage

Phase III

Target Class

Receptor

Safety

0.30

Druggability Analysis

Drug Development0.45

Structural Tractability0.85

Target Class0.70

Safety Profile0.30

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (1 compounds)

Therapeutic Areas:

Neuroinflammation Alzheimer's disease Parkinson's disease Neurodegeneration Sepsis with CNS involvement Neurotrauma

Druggability Rationale: TLR4 is highly druggable (0.80 score) due to its well-characterized extracellular domain, abundant structural data (25 PDB structures at 1.7 Å resolution), and proven tractability with small molecule antagonists and antibodies. The receptor's established role in neuroinflammation and precedent with Eritoran in clinical trials (despite Phase 3 failure) demonstrates feasibility of pharmacological modulation, though efficacy rather than target accessibility remains the challenge.

Mechanism: Small molecule antagonist or antibody blocking TLR4-mediated neuroinflammatory signaling

Drug Pipeline (1 compounds)

Known Drugs:

Eritoran (failed_phase3) — Sepsis (neuroinflammation trials)

Structural Data:

PDB (25) ✓AlphaFold ✓Cryo-EM ✓

2Z62 2Z63 2Z64 2Z65 2Z66+20 more

UniProt: O00206

Binding Pocket Analysis:

TLR4 features a prominent hydrophobic lipid A binding pocket in the extracellular domain (MD-2 co-receptor interface), with well-defined sub-pockets for acyl chain accommodation revealed in high-resolution crystal structures. Small molecule antagonists typically target this pocket directly, while antibody therapeutics exploit conformational epitopes on the ectodomain to prevent TLR4-MD-2-LPS trimerization and downstream signaling.

🧬 3D Protein Structure

🧬 TLR4 — PDB 3ULB 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 moderate concern given TLR4's role as part of the TLR family (TLR1-10); off-target activation of related TLRs (particularly TLR2) could confound therapeutic outcomes or cause immune dysregulation. However, TLR4's unique MD-2 co-receptor requirement and LPS-binding pocket provide opportunities for selective small molecule antagonists targeting the specific lipid A binding site.