Druggability & Clinical Context
Druggability
Low
Score: 0.29
Druggability Analysis
Structural Tractability0.30
Key Metrics
PDB Structures:
0
Known Drugs:
1
Approved:
0
In Clinical Trials:
0
Drug Pipeline (1 compounds)
1 Preclinical
Therapeutic Areas:Niemann-Pick disease Alzheimer's disease Neurodegenerative diseases Lipid storage disorders Metabolic diseases Neuroinflammation
Druggability Rationale: SGMS1 presents low druggability (0.30 score) despite being an enzyme class with established precedent, primarily due to lack of available crystal structures (0 PDB entries) and limited structural characterization beyond AlphaFold predictions. The single known preclinical inhibitor (D609) suggests the active site is targetable, but the absence of high-resolution structural data significantly hampers rational drug design and optimization efforts.
Mechanism: SGMS1 inhibitors would block the transfer of phosphocholine from phosphatidylcholine to ceramide, reducing sphingomyelin synthesis and potentially decreasing membrane rigidity and inflammatory signaling. This mechanism could modulate membrane-dependent cellular processes and may have therapeutic effects in lipid storage disorders and metabolic diseases.
Drug Pipeline (1 compounds)
1 Preclinical
Known Drugs:D609 (preclinical) — Tricyclodecan-9-yl xanthate, SMS inhibitor
Structural Data:PDB —AlphaFold ✓Cryo-EM —
Binding Pocket Analysis:The binding pocket characteristics remain poorly defined due to absence of experimentally resolved structures; however, the mechanism requires accommodation of both phosphatidylcholine donor and ceramide acceptor substrates, suggesting a substrate-binding pocket with distinct recognition elements for phospholipid headgroups. AlphaFold modeling may provide preliminary insights into active site topology, but experimental validation through X-ray crystallography or cryo-EM would be critical for structure-based drug design.
Selectivity & Safety Considerations
SGMS1 has a closely related homolog (SGMS2) with overlapping substrate specificity, presenting a significant selectivity challenge for achieving isoform-selective inhibition. Off-target modulation of sphingomyelin synthesis through SGMS2 could compromise therapeutic specificity and necessitates careful pharmacological profiling to avoid unintended lipid metabolic disruption.
Clinical Trials (8)
Relevant trials from ClinicalTrials.gov
By Phase
NA: 5 · PHASE1: 1 · PHASE2: 1 · Unknown: 1
NA
NCT00486551
n=26
Tourette Syndrome, Chronic Tic Disorder, Oppositional Defiant Disorder
Interventions: Anger control training
Sponsor: Yale University | Started: 2001-08
NA
NCT06909045
n=130
Deep Brain Stimulation, Parkinson Disease
Interventions: Adaptive DBS, Continue DBS
Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC | Started: 2026-01-27
PHASE1
NCT00843739
n=90
Parkinson's Disease
Interventions: EMST - Active Treatment, sham EMST
Sponsor: University of Florida | Started: 2004-01
Unknown
NCT03292575
n=441
Stroke
Interventions: Anticoagulants
Sponsor: Centre Hospitalier Universitaire Dijon | Started: 2016-01
NA
NCT01924312
n=80
Cerebrovascular Disease, Mild Cognitive Impairment
Interventions: Heart Health Intervention
Sponsor: Gregory Jicha, 323-5550 | Started: 2013-05
NA
NCT06306365
n=35
Executive Functions
Interventions: Modern board game-based learning
Sponsor: European University Miguel de Cervantes | Started: 2024-02-07
NA
NCT02260167
n=25
Alzheimer's Disease, Dementia
Interventions: A mix of natural treatments and medicati
Sponsor: Practitioners Alliance Network | Started: 2014-09
PHASE2
NCT03987295
n=33
Frontotemporal Dementia
Interventions: AL001
Sponsor: Alector Inc. | Started: 2019-09-27