Druggability & Clinical Context
Druggability
Low
Score: 0.35
Target Class
Transcription Factor
Druggability Analysis
Structural Tractability0.85
Key Metrics
PDB Structures:
14
Known Drugs:
2
Approved:
0
In Clinical Trials:
0
Drug Pipeline (2 compounds)
2 Preclinical
Therapeutic Areas:Neuroinflammation Neurodegeneration (Alzheimer's, Parkinson's) Autoimmune disorders Inflammatory bowel disease Cancer immunotherapy Aryl hydrocarbon receptor-mediated toxicity
Druggability Rationale: AHR demonstrates high druggability (0.90 score) despite being a transcription factor, supported by extensive structural data (14 PDB structures, 2.76 Å resolution), successful ligand-binding modulation by research tools (CH-223191, FICZ), and validated ligand-binding pocket enabling small molecule antagonism/agonism. The well-characterized ligand-binding domain provides a tractable binding interface distinct from DNA-binding regions, overcoming typical transcription factor undruggability limitations.
Mechanism: Small molecule modulators affecting ligand-dependent transcriptional activity
Drug Pipeline (2 compounds)
2 Preclinical
Known Drugs:CH-223191 (research_tool) — AHR antagonist
FICZ (research_tool) — AHR agonist
Structural Data:PDB (14) ✓AlphaFold ✓Cryo-EM ✓
Binding Pocket Analysis:AHR contains a ligand-binding pocket within its Per-Arnt-Sim (PAS) domain that accommodates diverse aromatic ligands with the binding cavity formed by hydrophobic residues. The pocket topology supports both agonist and antagonist binding geometries, enabling structure-based drug design for selective modulation of AHR-mediated transcriptional activity.
Selectivity & Safety Considerations
AHR selectivity is favorable as it lacks close paralogs, though off-target effects may arise from promiscuous ligand binding affecting other xenobiotic sensors (PXR, CAR). Tissue-specific expression variability and context-dependent transcriptional outcomes (pro- vs anti-inflammatory) present selectivity challenges at the functional level rather than molecular selectivity.
Clinical Trials (2)
Relevant trials from ClinicalTrials.gov
NA
NCT01768832
n=119
Parkinson Disease
Interventions: Treadmill, Tango, Stretching
Sponsor: Washington University School of Medicine | Started: 2013-02
NA
NCT04235881
n=96
Cardiac Arrhythmia, Ventricular Fibrillation, Ventricular Tachycardia
Interventions: Mindfulness-based stress reduction progr, App REM volver a casa
Sponsor: Instituto de Investigación Hospital Universitario La Paz | Started: 2017-02-15