Network pharmacology–driven identification of PTP1β and rational design of simufilam-based allosteric inhibitors for neuroprotection in Alzheimer’s disease

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that predominantly affects elderly people and is characterized by cognitive decline and dementia. Protein tyrosine phosphatase-1B (PTP1B) is known to modulate pro-inflammatory mediators, and its overexpression in the brain has been implicated in AD-associated neuroinflammation. This study explores the mechanism of A20, A26, and co-crystal-designed compound targeting non-competitive allosteric PTP1B enzyme inhibition for AD therapy using network pharmacology and computational studies. Protein-protein interaction was designed for 128 active targets by STRING database and Cytoscape software. Further, active target-associated pathways analysed using ClueGO plugin Cytoscape software and the Reactome online public domain server. The non-competitive allosteric PTP1B inhibition through the design of Simufilam derivatives, with particular emphasis on A20, which is predicted to bind at the non-competitive allosteric site of the PTP1B protein (PDB ID: 1T49), involves α3, α6, and α7 helices that influence the WPD loop orientation. The proposed non-competitive allosteric binding mode is based on computational evidence and for that further experimental validation would be required to conclusively confirm binding of the designed compounds within this regulatory region. Using in-silico approaches, including molecular docking, identified A20 with the most favourable predicted binding energy score (−10.8 kcal/mol) compared to other derivatives. Molecular dynamics simulations further indicated structural stability of the PTP1B-A20, 26, and co-crystal complex, with consistent RMSD, RMSF, H-bond, Rg, and SASA. Principal component analysis suggested that A20 restricts conformational flexibility; hence MM-PBSA analysis displayed its stable binding free energies. Density functional theory (DFT) calculation characterized the polarity, stability, and reactivity of A20 studies supported its favourable electronic configuration. Overall, A20 displayed superior calculated binding energies, trajectory stability, and predicted drug-likeness, positioning it as a promising lead candidate for future empirical validation in AD research.