Structure-based virtual screening to identify potential lipase inhibitors to reduce lipid storage in Wolman disorder
Karthick Vasudevan1, S Udhaya Kumar2, A Mithun1
1Department of Biotechnology, School of Applied Sciences, REVA University, Bengaluru, Karnataka, India.
Insights
Wolman disorder, a lipid accumulation disease, may be treated with dl-alpha-Tocopherol-13C3. This molecule shows promise in stabilizing the G87V mutant lysosomal acid lipase (LAL) form, offering a potential therapeutic avenue.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Wolman disorder (WD) is a rare genetic disease caused by lysosomal acid lipase (LAL) deficiency.
- WD leads to severe lipid accumulation in multiple organs, causing early mortality.
- The G87V mutation in the LIPA gene is a primary cause of WD.
Purpose of the Study:
- To identify potential therapeutic agents for Wolman disorder.
- To investigate the efficacy of tocopherol derivatives against the LIPA G87V mutation.
Main Methods:
- Virtual screening of compounds, including tocopherol derivatives.
- Molecular docking of lead compounds with native and mutant LIPA.
- Assessment of ADME and toxicity parameters.
- Molecular dynamics simulations to evaluate lead molecule stability.
Main Results:
- dl-alpha-Tocopherol-13C3 was identified as a potential lead molecule.
- The molecule demonstrated stability and effectiveness against the LIPA G87V mutant.
- Screened compounds exhibited favorable ADME and toxicity profiles.
Conclusions:
- dl-alpha-Tocopherol-13C3 is a promising candidate for treating Wolman disorder.
- Targeting the LIPA G87V mutation with tocopherol derivatives offers a potential therapeutic strategy.
Abstract:
Wolman disorder (WD) was first described in Iranian-Jewish (IJ) children, and it is caused by a deficiency of the lysosomal acid lipase (LAL). Newborns with WD are healthy and active at birth but soon develop severe malnutrition symptoms and often die before 1 year. In particular, spleens, livers, bone marrows, intestines, adrenal glands, and lymph nodes accumulate harmful amounts of lipids. G87V mutation in LIPA is responsible for Wolman disorder. Some reports suggest that δ-tocopherol can reduce lipid accumulation in cholesterol storage disorders. Hence, we used δ-tocopherol for the virtual screening process in this study. Initially, the lead compounds were docked with native and G87V mutant LIPA. Subsequently, the ADME and toxicity parameters for screened compounds were determined to ensure the safety profiles. Finally, the molecular dynamics simulations result indicated that dl-alpha-Tocopherol-13C3, a molecule obtained from the PubChem database, is identified as a potential and stable lead molecule that could be effective against the G87V mutant form of LIPA.
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