Computational evaluation of EPA-PC binding to GCase in neuronopathic Gaucher disease

Gaucher disease (GD) is a lysosomal storage disorder caused by deficient acid β-glucosidase (GCase) activity and consequent accumulation of glucosylceramide. Current enzyme replacement and substrate reduction therapies improve several systemic manifestations but have limited impact on neuronopathic disease, motivating evaluation of alternative molecular strategies. This study computationally assessed the interaction of EPA-phosphatidylcholine (EPA-PC), a marine-derived omega-3 phospholipid, with human GCase (PDB ID: 2NSX). The protein structure was examined by Ramachandran analysis and hydrophobicity profiling, followed by AutoDock Vina engine docking at the proposed hydrophobic i-face. EPA-PC showed a docking score of -5.5 kcal/mol under the applied protocol. Independent PLIP profiling of the docked complex identified predominantly hydrophobic contacts, one hydrogen bond involving Phe347, and Arg395-mediated salt-bridge interactions. A single 200 ns molecular dynamics trajectory of the EPA-PC-GCase complex showed an apparent backbone RMSD plateau of approximately 0.35-0.40 nm and a radius of gyration near 2.4 nm without a sustained increase in global compactness or solvent exposure. These observations support persistence of the modelled complex during the reported trajectory but do not establish ligand-induced GCase stabilisation or pharmacological-chaperone activity. In silico ADMET profiling also indicated substantial liabilities, including very high plasma protein binding and predicted hERG-related risk. EPA-PC should therefore be regarded as a preliminary lipid-protein interaction model requiring comparative simulations, independent replicates, and experimental validation.