Bioinformatics and network pharmacological characterization of xanomeline for therapeutic intervention in areca nut...

BackgroundAreca nut, a known carcinogen and addictive substance continues to be consumed globally. There is a lacuna in cessation strategies to combat areca-addiction. Xanomeline, a synthetic derivative of arecoline has gained significance in recent times for treatment of chronic neurological disorders.ObjectivesTo conduct an in-silico comparison between arecoline and xanomeline for identifying possible interactions that may unveil development of future intervention strategies.MethodsAn integrative in-silico approach was employed, including physicochemical profiling, toxicity prediction, molecular docking(MD), molecular dynamics simulation(MDS), and network pharmacology comparing arecoline and xanomeline. Docking was performed against muscarinic (CHRM1-5) and nicotinic (CHRNA3/4/7, CHRNB2/4) receptor subtypes relevant to cholinergic signaling and addiction. MDS was used to assess protein ligand interactions.ResultsXanomeline demonstrated superior binding affinity across most cholinergic targets, particularly CHRM1 (-6.2 kcal/mol), compared with arecoline (-4.4 kcal/mol). Both ligands exhibited stable RMSD trajectories, although xanomeline complexes showed comparatively reduced RMSF fluctuations. Xanomeline demonstrated higher plasma-protein-binding (PPB) (61.72%) than arecoline (12.740%), higher probability of blood-brain-barrier (BBB) penetration (0.992 cm/s) than arecoline (0.89 cm/s). AMES toxicity showed moderate predicted mutagenic potential (0.625) for arecoline and low predicted mutagenic potential (0.024) for xanomeline.ConclusionWithin the limitations of this in-silico investigation, xanomeline exhibited stronger binding affinity for addiction-related cholinergic receptors, improved stability in MDS, low predicted mutagenic potential and better CNS distribution characteristics than arecoline. These findings support the potential of xanomeline to modulate cholinergic pathways implicated in areca nut dependence and addiction and warrants further experimental validation as a promising pharmacological intervention strategy.