What question did this study set out to answer?

The study aims to identify therapeutic signatures and potential inhibitors for PLOSL through a systems biology approach.

February 22, 2026Open Access

System biology and network-based approach to identify the therapeutic signatures and potential inhibitors against polycystic lipomembranous osteodysplasia with Sclerosing Leukoencephalopathy

Key Points

The study aims to identify therapeutic signatures and potential inhibitors for PLOSL through a systems biology approach.
Employed Network Analyst tools for gene expression profiling.
Conducted survival analysis using Cytoscape to validate hub genes.
Utilized X2K online tool to examine regulatory kinases and protein interactions.
Performed molecular docking studies with AMG-131 and Elafibranor against PPARG.
Identified 53 differentially expressed genes with PPARG and AIF1 having the highest degree scores.
Demonstrated binding affinities for AMG-131, Elafibranor, and Rosiglitazone of -7.2, -7.4, and -7.6 kcal/mol, respectively.
Stability of the enzyme complex was shown with a mean RMSD of 2.95 Å for AMG-131 and 2.93 Å for Elafibranor.
Highlighted key enzyme residues (Arg76, Leu28, Leu118) critical for binding interactions.

Abstract

Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL), often recognized as Nasu-Hakola disease, is an uncommon autosomal recessive systemic condition described by numerous bone lesions that resemble cysts and progressive early-onset dementia. One novel way to find possible drug targets is to use Network Analyst tools for network-based gene expression profiling. Identifying the target hub genes, essential for the initiation and progression of PLOSL, is validated by the significance level (p-score) attained using Cytoscape in the survival analysis of the major central genes. The X2K online tool also examined the regulatory kinases that formed the interaction between protein molecule networks. Out of the 53 genes obtained to be differentially expressed, PPARG and AIF1 had the greatest degree score, followed by C1QA with 5 degrees and SIGLEC1 and MSR1 with 4 degrees. Furthermore, Molecular docking of target PPARG gene with AMG-131 and Elafibranor drugs, having the chemical formulas 2-2,6-dimethyl-4-[(E)-3-(4-methylsulfanylphenyl)-3-oxoprop-1-enylphenoxy], and 3,5-dichloro-4-quinolin-3-yloxyphenyl) benzenesulfonamide, along control (Rosiglitazone (S) shows binding affinities of −7.2 kcal/mol, −7.4 kcal/mol, and −7.6 kcal/mol respectively. The enzyme remained extremely stable in the complex throughout 200 ns, with a mean Root Mean Square Deviation (RMSD) of 2.95 Å for the AMG-131 complex system and 2.93 Å against the Elafibranor complex system. Root Mean Square Fluctuation (RMSF) anticipated steady behavior with average RMSD for the active site residues in the docked system. Arg76 and Leu28leu Leu118 were shown to be essential enzyme residues for binding, anchoring, and bridging strong hydrogen and hydrophobic interactions between the enzyme and the inhibitor, according to the Radial Distribution Function (RDF). These results broadened our knowledge of putative biomarkers for PLOSL diseases, and an experimental strategy will improve our results even more in the future.

System biology and network-based approach to identify the therapeutic signatures and potential inhibitors against polycystic lipomembranous osteodysplasia with Sclerosing Leukoencephalopathy

Key Points

Abstract

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