PARP1

Poly [ADP-ribose] polymerase 1

Score: 0.657 Price: $0.66 Medium Druggability Status: active Wiki: PARP1

🧠 Neurodegeneration

HYPOTHESES

PAPERS

KG EDGES

410

DEBATES

3D Protein Structure

🧬 PARP1 — PDB 4DQY Click to expand

Experimental structure from RCSB PDB | Powered by Mol*

Druggability & Clinical Context

Druggability

Medium

Score: 0.62

Clinical Stage

Approved

Target Class

Enzyme

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 (3 compounds)

3 Approved

Therapeutic Areas:

BRCA-mutated cancers Ovarian cancer Neurodegeneration (parthanatos-mediated) Ischemic stroke Traumatic brain injury Neurodegenerative diseases (ALS, Parkinson's disease) Chronic neuroinflammation

Druggability Rationale: PARP1 is highly druggable due to its well-defined catalytic domain with a deep ATP-binding pocket, demonstrated by 97 PDB structures at 1.5Å resolution and three FDA-approved inhibitors (olaparib, niraparib, rucaparib) already in clinical use. The enzyme's established role in DNA repair and validated mechanism of action as a competitive inhibitor provides a clear therapeutic window for both oncology and neuroprotection applications.

Mechanism: Competitive inhibitors of PARP1 enzymatic activity blocking DNA repair

Drug Pipeline (3 compounds)

3 Approved

Known Drugs:

Olaparib (approved) — BRCA-mutated cancers

Niraparib (approved) — ovarian cancer

Rucaparib (approved) — ovarian cancer

Structural Data:

PDB (97) ✓AlphaFold ✓Cryo-EM ✓

2COK 2CR9 2CS2 2JVN 2L30+92 more

UniProt: Q05D33

Binding Pocket Analysis:

PARP1 contains a highly conserved NAD+-binding pocket within the catalytic domain that serves as the primary binding site for competitive inhibitors, characterized by aromatic residues and hydrogen bond donors/acceptors. The pocket's accessibility and well-defined geometry (evidenced by extensive structural data including AlphaFold and cryo-EM data) make it amenable to rational drug design with high ligand binding affinity and specificity.

🧬 3D Protein Structure

🧬 PARP1 — PDB 4DQY Click to expand interactive 3D viewer

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

Selectivity & Safety Considerations

PARP1 inhibition presents moderate selectivity challenges due to structural homology with other PARP family members (PARP2-PARP17), risking off-target activity; however, existing approved drugs demonstrate achievable selectivity through careful chemical design. Isoform-selective inhibitors have been developed to minimize off-target effects and potentially improve therapeutic index in neuroprotection applications.