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

## TL;DR

This paper uses systems biology and network analysis to identify potential drug targets and inhibitors for PLOSL, a rare genetic disease affecting bones and the brain.

## Contribution

The study introduces a network-based approach to identify hub genes and potential inhibitors for PLOSL, validated through molecular docking and stability analysis.

## Key findings

- PPARG and AIF1 were identified as key hub genes with the highest degree scores in the PLOSL network.
- AMG-131 and Elafibranor showed strong binding affinities to PPARG with RMSD values indicating stable complexes.
- Arg76 and Leu118 were found to be crucial for hydrogen and hydrophobic interactions in the enzyme-inhibitor complex.

## 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-enyl]phenoxy], 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.