Computational evaluation of carnosic acid as a 4EY7 inhibitor for potential anti-Alzheimer therapy.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized in part by cholinergic dysfunction resulting from excessive acetylcholinesterase (AChE) activity. Although currently approved AChE inhibitors provide symptomatic relief, their clinical benefits remain modest and are often associated with adverse effects. Natural products represent an important source of structurally diverse bioactive compounds with potential therapeutic relevance. In this study, we computationally evaluated carnosic acid, a diterpene from Rosmarinus officinalis, as a potential AChE inhibitor using molecular docking, molecular dynamics (MD) simulations, normal mode analysis (NMA), and ADME profiling. Docking against the human AChE crystal structure (PDB ID: 4EY7) yielded a binding energy of -6.5 kcal/mol, comparable to reference phytochemicals evaluated under identical conditions. Interaction analysis revealed hydrogen bonding and hydrophobic contacts within the catalytic anionic site. A 100 ns MD simulation demonstrated structural stability of the carnosic acid-AChE complex, supported by stable RMSD, RMSF, radius of gyration (Rg), solvent-accessible surface area (SASA), and persistent hydrogen bonding patterns. NMA indicated coordinated motions and low deformability, suggesting stable complex formation. ADME prediction showed acceptable drug-likeness with one Lipinski rule violation but indicated limited gastrointestinal absorption and lack of predicted blood-brain barrier permeability, representing potential developmental challenges. Overall, these in silico findings suggest that carnosic acid exhibits moderate binding affinity and stable interaction with AChE, supporting further experimental validation to assess its therapeutic potential in AD.