Licochalcone A as Novel Multitarget Inhibitors via AChE, BuChE, and Synapsin III for Therapeutic Intervention Against Alzheimer’s Disease: Computer‐Aided Drug Design

Alzheimer’s disease (AD) is characterized by key pathological features, including cholinergic dysfunction, amyloid‐beta (Aβ) aggregation, and disrupted synaptic transmission, positioning proteins such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Synapsin III as critical targets for therapeutic strategies. Targeting multiple AD‐associated proteins simultaneously can alter disease progression and improve cognitive function by addressing tau pathology and cholinergic deficiencies. Multitarget drugs (MTDs) that simultaneously target multiple subpathologies are expected to be a better approach. However, current AD treatments are highly limited, with existing medications showing minimal efficacy against this persistent condition. To develop novel multitarget inhibitors, we employed molecular docking and dynamic analyses. The drug‐likeness and pharmacokinetic profiles of selected molecules were evaluated using the Lipinski filter and ADMET analysis. Licochalcone A and piperine exhibited superior binding affinity to AChE, BuChE, and Synapsin III compared to controls (tacrine and donepezil). Licochalcone A showed higher binding affinity from docking results, which were −12.58, −11.54, and −11.53 kcal/mol for AChE, BuChE, and Synapsin III structures, respectively. RMSD results showed that licochalcone A has a more balanced and stable profile with a lower value than piperine and is acceptable in terms of stable complex formation. The RMSD values for AChE, BuChE, and Synapsin III bound with licochalcone A molecule were 0.16, 0.17, and 0.25 nm, respectively. Molecular dynamics simulations revealed stable RMSF, Rg, SASA, and hydrogen bond profiles for all systems. Furthermore, the pharmacological similarity and pharmacokinetic properties of these compounds demonstrated favorable drug‐like properties, which warrant further in vitro studies to confirm their therapeutic potential for AD.