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The present theoretical\u2010experimental work improves the drug\u2018s residence time without reducing the inhibition effect, thus providing a 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 a catalytic anionic site, and its release from AChE needs only \u223c8.6\u2005kcal\/mol. Both of these 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\u2010release ability for inhibitors. The compound with \u201cspecific\u2010ring\u2010chain\u2010ring\u201d framework with detailed beneficial modification scheme is summarized, which may improve the residence time of the 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 experimental combinations probably provide a train of thought from both static and dynamic views to modify or design appropriate inhibitors on the basis of specific binding and transportation features.<\/jats:p>","DOI":"10.1002\/chem.202203363","type":"journal-article","created":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T09:59:06Z","timestamp":1677232746000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Static Binding and Dynamic Transporting\u2010Based Design of Specific Ring\u2010Chain\u2010Ring Acetylcholinesterase Inhibitor: From Galantamine to Natural Product"],"prefix":"10.1002","volume":"29","author":[{"given":"Zhiyang","family":"Zhang","sequence":"first","affiliation":[{"name":"The Key Laboratory of Natural Medicine and Immuno-Engineering Henan University  Kaifeng 475004 (P. R. 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