Zhang_2023_Chemistry__e202203363

Acetylcholinesterase (AChE) is a key target for the current symptomatic treatment of Alzheimer's disease, and galantamine is a clinical anticholinesterase drug with transiently acting characteristic and good selectivity for AChE. The present theoretical-experimental work improves the drug's residence time without reducing inhibition effect, thus provides crucial breakthrough for modifying the inhibitor of AChE with better-kinetic behavior. The static binding and dynamic delivery properties acquired from atomic view reveal that the galantamine simply occupies catalytic anionic site, and its release from AChE needs only ~ 8.6 kcal/mol. Both of them may cause the short residence time of galantamine. The hotspots and most favorable transport mechanism are identified, and the hydrogen bond and aromatic stacking interactions are observed to play crucial roles for galantamine binding and release in AChE. The typical peripheral anionic site arisen at the delivery process would provide another key occupation to enhance the anti-release ability for inhibitors. The compound with "specific-ring-chain-ring" framework with detail beneficial modify scheme is summarized, which may improve the residence time of inhibitor in AChE. The thermodynamic and dynamic properties of galantamine derivatives are also studied. Based on dictamnine, a natural alkaloid, two novel eligible derivatives are designed, synthesized and evaluated, which verifies our prediction. Multiple computational approaches and experiment combination probably provide a train of thought from static and dynamic view to modify or design appropriate inhibitor on the basis of specific binding and transportation features.