Structure-based virtual screening to identify potential lipase inhibitors to reduce lipid storage in Wolman disorder.

Adv Protein Chem Struct Biol

Laboratory of Integrative Genomics, Department of Integrative Biology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India. Electronic address:

Published: January 2023

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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http://dx.doi.org/10.1016/bs.apcsb.2022.10.010DOI Listing

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