SIRT3

NAD-dependent deacetylase sirtuin-3, mitochondrial

Score: 0.717 Price: $0.50 Medium Druggability Status: active Wiki: SIRT3

HYPOTHESES

PAPERS

KG EDGES

658

DEBATES

3D Protein Structure

🧬 SIRT3 — PDB 4FVT Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.61

Clinical Stage

Phase II

Target Class

Enzyme

Safety

0.75

Druggability Analysis

Drug Development0.30

Structural Tractability0.85

Target Class0.85

Safety Profile0.75

Key Metrics

PDB Structures:

Known Drugs:

Approved:

In Clinical Trials:

Drug Pipeline (4 compounds)

Therapeutic Areas:

Alzheimer's disease Parkinson's disease Neurodegeneration Mitochondrial dysfunction Oxidative stress-related disorders Age-related cognitive decline Neuroinflammation

Druggability Rationale: SIRT3 is moderately tractable (0.68 score) as an enzyme target with a well-characterized NAD+-binding pocket and established precedent for activation via both direct small-molecule activators (Honokiol) and indirect NAD+ precursor approaches (NR, NMN). The existence of clinical-stage compounds and the target's clear enzymatic mechanism support small-molecule druggability, though achieving selective SIRT3 activation over other sirtuins remains a key challenge.

Mechanism: Enzyme activation — enhancing SIRT3 deacetylase activity restores mitochondrial protein function and reduces oxidative stress

Drug Pipeline (4 compounds)

Known Drugs:

Nicotinamide Riboside (NR) (Clinical trials)

Nicotinamide Mononucleotide (NMN) (Clinical trials)

Honokiol (Preclinical)

Resveratrol (Phase II)

Structural Data:

PDB (30) ✓AlphaFold ✓Cryo-EM —

3GLR 4BN5 4HD8 5D7N 4FVT+25 more

UniProt: Q9NTG7

Binding Pocket Analysis:

SIRT3 contains a conserved NAD+-binding pocket characteristic of the sirtuin family, with the catalytic domain accommodating both NAD+ cofactor and acetylated protein substrates. Direct activators likely bind allosteric sites distinct from the NAD+ pocket, while NAD+ precursors work by increasing local NAD+ availability rather than direct binding.

🧬 3D Protein Structure

🧬 SIRT3 — PDB 4FVT Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

SIRT3 selectivity is challenging due to structural homology with other NAD+-dependent sirtuins (SIRT1, SIRT4, SIRT5); off-target effects on cytoplasmic sirtuins could confound mitochondrial-specific outcomes. Mitochondrial localization provides a degree of inherent selectivity advantage, allowing indirect activation via NAD+ precursors to preferentially benefit SIRT3 without requiring direct isoform selectivity.