posted on 2020-03-05, 20:40authored byMonica
A. Silva, Alessandra S. Kiametis, Werner Treptow
Donepezil
is a second generation acetylcholinesterase (AChE) inhibitor
for treatment of Alzheimer’s disease (AD). AChE is important
for neurotransmission at neuromuscular junctions and cholinergic brain
synapses by hydrolyzing acetylcholine into acetate and choline. In vitro data support that donepezil is a reversible, mixed
competitive and noncompetitive inhibitor of AChE. The experimental
fact then suggests a more complex binding mechanism beyond the molecular
view in X-ray models resolved at cryogenic temperatures that show
a unique binding mode of donepezil in the active site of the enzyme.
Aiming at clarifying the mechanism behind that mixed competitive and
noncompetitive nature of the inhibitor, we have applied molecular
dynamics (MD) simulations and docking and free-energy calculations
to investigate microscopic details and energetics of donepezil association
for conditions of substrate-free and -bound states of the enzyme.
Liquid-phase MD simulation at room temperature shows AChE transits
between “open” and “closed” conformations
to control accessibility to the active site and ligand binding. As
shown by docking and free-energy calculations, association of donepezil
involves its reversible axial displacement and reorientation in the
active site of the enzyme, assisted by water molecules. Donepezil
binds equally well the main-door anionic binding site PAS, the acyl
pocket, and the catalytic site CAS by respectively adopting outward–inward–inward orientations regardless of substrate occupancy–the overall
stability of that reaction process depends however on co-occupancy
of the enzyme being preferential for its substrate-free state. All
together, our findings support a physiologically relevant mechanism
of AChE inhibition by donepezil involving multistable interactions
modes at the molecular origin of the inhibitor’s activity.