Druggability & Clinical Context
Druggability
Low
Score: 0.43
Druggability Analysis
Structural Tractability0.70
Key Metrics
PDB Structures:
3
Known Drugs:
1
Approved:
0
In Clinical Trials:
0
Drug Pipeline (1 compounds)
Therapeutic Areas:Neurodegenerative diseases (Alzheimer's disease, cognitive decline) Blood-brain barrier dysfunction Vascular cognitive impairment Fibrotic diseases (pulmonary/cardiac fibrosis) Neuroinflammation Vascular pathology
Druggability Rationale: LOX (lysyl oxidase) represents a moderately promising neurodegeneration drug target with medium druggability, primarily due to its critical role in extracellular matrix remodeling and crosslinking. The availability of structural data and existing small molecule inhibition strategies like simtuzumab suggest potential therapeutic approaches, though significant additional validation would be required to establish neurodegeneration-specific efficacy. Structural insights from PDB entries and AlphaFold predictions provide a foundation for rational drug design targeting its enzymatic active site.
Mechanism: Small molecule inhibition of lysyl oxidase enzymatic activity
Drug Pipeline (1 compounds)
Known Drugs:Simtuzumab (Clinical) — Fibrotic diseases
Structural Data:PDB (3) ✓AlphaFold ✓Cryo-EM —
Binding Pocket Analysis:The active site contains a copper cofactor coordinated by histidine and tyrosine residues, creating a catalytic pocket suitable for substrate binding and inhibitor design. PDB structures (4G32, 4G33, 4RPE) reveal a well-characterized active site geometry that accommodates both natural substrates (lysine residues on collagen/elastin) and synthetic inhibitors, with additional allosteric sites potentially available for modulation.
Selectivity & Safety Considerations
LOX shares structural homology with the copper-dependent amine oxidase family (LOX-like proteins: LOXL1-4), presenting significant isoform selectivity challenges for small molecule inhibitors. Off-target inhibition of monoamine oxidases (MAO-A/B) and other oxidative enzymes must be carefully monitored, particularly in CNS applications where neurochemical balance is critical.
Clinical Trials (6)
Relevant trials from ClinicalTrials.gov
PHASE2
NCT01452308
n=20
Liver Fibrosis
Interventions: Simtuzumab
Sponsor: Gilead Sciences | Started: 2011-11
PHASE2
NCT02466516
n=72
Non-Alcoholic Steatohepatitis (NASH)
Interventions: SEL, SIM
Sponsor: Gilead Sciences | Started: 2015-06-08
PHASE2
NCT01672853
n=235
Primary Sclerosing Cholangitis (PSC)
Interventions: Simtuzumab, Placebo
Sponsor: Gilead Sciences | Started: 2013-03-04
PHASE2
NCT01479465
n=266
Colorectal Cancer
Interventions: Simtuzumab, Placebo to match SIM, Leucovorin
Sponsor: Gilead Sciences | Started: 2011-12
PHASE2
NCT01672866
n=222
Liver Fibrosis Due to NASH
Interventions: Placebo, SIM
Sponsor: Gilead Sciences | Started: 2012-12-05
PHASE2
NCT01672879
n=259
Liver Fibrosis Due to NASH
Interventions: Placebo, SIM
Sponsor: Gilead Sciences | Started: 2012-10-29