A new structure-based virtual screening study has identified DL-alpha-Tocopherol-13C3 as a potentially effective molecule against excessive lipid storage in Wolman disease, a type of lysosomal acid lipase deficiency (LAL-D).

The study, published in Advances in Protein Chemistry and Structural Biology, noted that the molecule was found to bind specifically to the G87V mutant form of the lipase A gene (LIPA).

“By screening a vast virtual chemical space of small organic molecules to find compounds that can block a specific disease and have the greatest possibility of being a successful drug candidate, the ultimate goal of virtual screening is to reduce time and minimize expense,” the authors wrote. “Hence in our study, we aimed to conduct a computational screening of potential compounds for the treatment of Wolman disease.”


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The research team virtually modeled the 3D structure of the G87V LIPA mutant along with the 3D structure of 130 nonmutagenic, nontumorigenic compounds from the PubChem database. The aim was to assess the ability of the potentially therapeutic compounds to bind with the gene in a stable manner and lead to the inhibition of lipid storage, which is essential to effectively treating Wolman disorder.

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The authors performed molecular docking studies to explore a variety of potential ligand conformations and intermolecular interactions between the target gene and the screened compounds. A greater number of hydrogen bonds between the protein and the ligand suggested better binding efficiency of the complex.

The virtual screening approach identified successful and consistent binding of the DL-alpha-Tocopherol-13C3 compound with the mutant form of LIPA by showing a high number of hydrogen bonds and the crucial interactions required to inhibit the storage of excess cholesteryl esters and triglycerides in the lysosome.

The authors concluded that DL-alpha-Tocopherol-13C3 and similar compounds might be effective in the treatment of patients with Wolman disease and noted that biochemical experiments would help characterize the enzyme activity in these gene-compound complexes.

Reference

Vasudevan K, Udhaya Kumar S, Mithun A, et al. Structure-based virtual screening to identify potential lipase inhibitors to reduce lipid storage in Wolman disorder. Adv Protein Chem Struct Biol. Published online November 30, 2022. doi:10.1016/bs.apcsb.2022.10.010