Investigating the multifunctionality of fluorinated donepezil derivatives for Alzheimer's disease

Alzheimer's disease (AD) is the most common type of dementia, yet its precise etiology remains elusive. AD is a multifaceted disorder involved in the hydrolysis of the neurotransmitter acetylcholine and amyloid-beta (A(3) accumulation in the Alzheimer's brain. Despite FDA-approved single-target drugs showing potential, therapeutic efficacy in AD treatment remains deficient, urging the development of multifunctional drugs. In this study, we design fluorinated derivatives from a widely prescribed therapeutic candidate, donepezil. Employing a computational approach integrating molecular docking, molecular dynamics (MD) simulations, and density functional theory analysis, we modified the benzene moiety of donepezil with fluorine-based functional groups to enhance pharmacokinetic properties and anti-amyloid activity. Evaluation of mono, di-, and tri-fluorinated derivatives revealed adherence to Lipinski's rule of five and blood-brain barrier penetration. Docking scores for all the fluorinated derivatives are varied within -10.8 to -11.7 kcal/mol, indicating binding affinity of fluorinated derivatives to acetylcholinesterase. The fluorinated derivatives display halogen bonding interactions with His 440 of catalytic site of enzyme. Among the mono-, di-, and tri-fluorinated derivatives, the meta-F(-25.2 f 2.9 kcal/mol), 3,5-F (-36.6 f 2.5 kcal/mol) and 2,4,6-F (-39.3 f 2.1 kcal/mol) derivative, respectively, show strong binding affinity towards the AChE. These fluorinated derivatives are further assessed against both A(342 protofibrils and the full-length fibrils, demonstrating a strong binding affinity. The impact of fluorinated derivatives on secondary structural transformation is greater in the pentamer A(342 protofibrils compared to A(3 fibrils, suggesting inhibition of toxic amyloid beta-sheet conformations in the A(342 protofibrils. Quantum chemical analysis highlighted the heightened structural chemical stability of novel lead fluorinated compounds, suggesting promising anti-AD potential. Overall, meta-F, 3,5-F, and 2,4,6-F derivatives might be a potential multitarget candidates for anti-AD activities, suggesting the need for continued drug design efforts in this direction.