esponse to Lipotoxicity as Potential Therapeutic Targets for Nervous System Diseases

Abstract

In keeping the brain in a steady state, astrocytes are crucial. Recent studies have shown 
that palmitic acid (PA) plays a key role in neurotoxicity by activating pro-inflammatory pathways. 
Also, metabolic switches (MSs) are regulators of metabolic pathways; they may worsen 
neurotoxicity; this makes them a viable therapeutic target, according to genomic-scale metabolic 
models and control theory. Using structural characterisation approaches, protein-protein 
interaction networks, and drug-protein interaction networks, we in silico evaluated these 
enzymatic MSs as prospective therapeutic targets. Five MSs (P00558, P04406, Q08426, P09110, 
and O76062) were found to be functionally linked to drug targets in the nervous system. These 
MSs may be indirectly regulated by certain neurological drugs, including those with 
polypharmacological potential, such as Haloperidol, Trifluoperazine, Disulfiram, and 
Trifluperidol. In addition, four microsomes (P00558, P04406, Q08426, and P09110) have 
druggable potential ligand-binding or allosteric cavities. Based on our findings, it seems that 
P00558 (phosphoglycerate kinase 1), P04406 (glyceraldehyde-3-phosphate dehydrogenase), 
Q08426 (peroxisomal bifunctional enzyme, enoyl-CoA hydratase and 3-hydroxyacyl CoA 
dehydrogenase), P09110 (peroxisomal 3-ketoacyl-CoA thiolase), and O76062 (Delta(14)-sterol 
reductase) are potential targets for the creation or repurposing of pharmacological compounds. 
These targets could modulate lipotoxic-altered metabolic pathways, opening up new possibilities 
for the treatment of neurological diseases and other related human conditions.