Evaluation of Ion Channel Blockers as Cholinesterase Inhibitors for Alzheimer's Disease: An Integrated In Vitro, In Silico, and DFT Study
ChemistrySelect, cilt.11, sa.32, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 11 Sayı: 32
- Basım Tarihi: 2026
- Doi Numarası: 10.1002/slct.74022
- Dergi Adı: ChemistrySelect
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Academic Search Ultimate (EBSCO)
- Anahtar Kelimeler: Alzheimer's disease, cholinesterase inhibitors, drug repurposing, ion channel blockers, molecular docking
- Bilecik Şeyh Edebali Üniversitesi Adresli: Evet
Özet
Alzheimer's disease (AD) is closely related to disruptions in the cholinergic system and is characterized by dysregulation in the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. In this study, the inhibitory effects of seven different ion channel blockers (verapamil, diazoxide, acarbose, diltiazem, azimilide, mexiletine, and naringenin) on AChE and BChE enzymes were evaluated through in vitro assays, molecular docking, ADME prediction, and density functional theory (DFT) calculations. Enzymatic assays revealed that azimilide showed a significant inhibitory effect on AChE (IC50 = 6.3 µM, KI = 12.37 µM) with competitive inhibition kinetics, whereas verapamil, diazoxide, diltiazem and azimilide caused a significant decrease in BChE enzyme activity (p < 0.001). Molecular docking studies supported these results; azimilide exhibited the highest binding affinity to AChE (−11.52 kcal/mol) among ion channel blockers, second only to the reference inhibitor donepezil (−15.42 kcal/mol). DFT analysis at B3LYP/def2-SVP level revealed that azimilide possesses the lowest HOMO–LUMO energy gap (3.26 eV) and highest electrophilicity index (ω = 3.74 eV), correlating with its superior enzyme inhibitory activity. ADME profiling demonstrated favorable drug-likeness properties and blood–brain barrier (BBB) permeability for most compounds. These findings suggest that ion channel blockers, particularly azimilide, may serve as potential therapeutic agents for neurodegenerative diseases.