Neutral ceramidase-active site inhibitor chemotypes and binding modes
Nicolas Coant1, John D Bickel2, Ronald Rahaim3
1Stony Brook University Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA.
Bioorganic Chemistry
|August 2, 2023
Summary
Researchers developed novel neutral ceramidase (nCDase) inhibitors that are not ceramide mimetics. These compounds show improved potency and solubility, offering a promising new therapeutic avenue for diseases involving ceramide metabolism.
Area of Science:
- Biochemistry
- Enzymology
- Drug Discovery
Background:
- Ceramides are crucial lipids involved in various biological functions and disease pathogenesis.
- Neutral ceramidase (nCDase) metabolizes ceramide to sphingosine, playing a key role in cellular and intestinal lipid homeostasis.
- Existing nCDase inhibitors, like C6-urea ceramide, suffer from poor potency, solubility, and limited aqueous stability.
Purpose of the Study:
- To identify and develop novel, non-ceramide mimetic inhibitors of neutral ceramidase (nCDase).
- To overcome the limitations of existing substrate-mimetic inhibitors.
- To explore potential therapeutic agents for conditions linked to aberrant ceramide metabolism.
Main Methods:
- High-throughput screening (HTS) to identify initial hit compounds.
- Biochemical and cell-based assays to evaluate inhibitor activity and specificity.
- In silico modeling, including DOCK screening and molecular simulations, to understand binding mechanisms.
Main Results:
- Identified small molecule nCDase inhibitors with novel pharmacophores, distinct from ceramide mimetics.
- These inhibitors demonstrated specificity for nCDase over related enzymes like acid/alkaline ceramidases and metalloproteases.
- Optimized inhibitors exhibited substrate competitiveness, cellular activity, and significantly improved potency and solubility compared to C6-urea ceramide.
Conclusions:
- Novel non-ceramide mimetic nCDase inhibitors have been successfully developed.
- These inhibitors possess favorable pharmacological properties, including enhanced activity and solubility.
- The findings present a promising new class of compounds for targeting nCDase in disease treatment.
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