Abstract
Alzheimer's disease (AD) causes dementia in most elderly individuals with cognitive and behavioral problems due to cholinergic synapse dysfunction. Thioridazine (TRZ) and perphenazine (PPZ) likely affect the acetylcholine (ACh) receptor and acetylcholinesterase (AChE) in the central nervous system (CNS) and improve the cholinergic system. This study aimed to determine the inhibitory effects of TRZ and PPZ on AChE using surface plasmon resonance (SPR) and molecular docking techniques to gain insight into the possible interaction mechanism between these medications and the enzyme. The SPR results indicated a high affinity of TRZ/PPZ to AChE (KD < 1 × 10−6 M). According to SPR results, increasing temperature decreases PPZ's binding strength to AChE while increasing the affinity of TRZ. Thermodynamic parameters demonstrated that hydrophobic interactions and hydrogen bonding are the main intermolecular forces between TRZ/PPZ and AChE. The results of the docking analysis were in good agreement with the experimental data, confirming only one binding site on AChE for TRZ and PPZ. PPZ showed a strong attachment to AChE due to its large negative binding energy (−10.58 kcal/mol). PPZ showed lower IC50 values toward AChE and TRZ, indicating a greater inhibitory effect on AChE.
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