NLRP3

NACHT, LRR and PYD domains-containing protein 3

Score: 0.644 Price: $0.64 Medium Druggability Status: active Wiki: NLRP3

🔥 Neuroinflammation 🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

2128

DEBATES

3D Protein Structure

🧬 NLRP3 — PDB 7LMZ Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.51

Clinical Stage

Approved

Target Class

Signaling Protein

Safety

0.50

Druggability Analysis

Drug Development0.75

Structural Tractability0.85

Target Class0.50

Safety Profile0.50

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (2 compounds)

1 Approved · 1 Preclinical

Therapeutic Areas:

Alzheimer's disease and neurodegeneration Parkinson's disease Amyotrophic lateral sclerosis (ALS) Gout and acute inflammatory arthropathies Acute kidney injury Pericarditis and autoinflammatory syndromes Atherosclerosis Type 2 diabetes

Druggability Rationale: NLRP3 demonstrates medium druggability (0.55) supported by existing approved drugs (colchicine) and investigational candidates (MCC950), robust structural characterization (25 PDB structures, cryo-EM data), and well-defined inflammasome assembly mechanisms. However, achieving selective NLRP3 inhibition without broad immunosuppression remains challenging, as the target is a large multi-domain signaling scaffold rather than a classical enzyme active site.

Mechanism: Small molecule inhibitors targeting NLRP3 inflammasome assembly or activation

Drug Pipeline (2 compounds)

1 Approved · 1 Preclinical

Known Drugs:

MCC950 (investigational) — inflammatory diseases

Colchicine (approved) — gout, pericarditis

Structural Data:

PDB (25) ✓AlphaFold ✓Cryo-EM ✓

2NAQ 6NPY 7ALV 7LFH 7PZC+20 more

UniProt: A0A7I2R3P8

Binding Pocket Analysis:

Structural data reveals NLRP3 lacks a classical ATP-binding active site; instead, small molecules bind allosteric pockets at domain interfaces (NACHT-LRR or PYD regions) to prevent inflammasome assembly and ASC recruitment. The best-characterized pocket accommodates compounds like MCC950 in the nucleotide-binding groove, stabilizing an inactive NLRP3 conformation.

🧬 3D Protein Structure

🧬 NLRP3 — PDB 7LMZ Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

NLRP3 selectivity is critical as off-target inhibition of related inflammasomes (NLRC4, AIM2) or broader NLR family members could impair protective immunity. Achieving selectivity is complicated by homologous NACHT and LRR domain architecture across the NLR family, though allosteric inhibitors targeting NLRP3-specific conformational states offer improved selectivity over direct competitive approaches.