Kinetic and structural studies on the interactions of Torpedo californica acetylcholinesterase with two donepezil-like rigid analogues

Journal of Enzyme Inhibition and Medicinal Chemistry

Luca Cariati¹  Antonio Procopio¹  Manuela Oliverio¹  Doriano Lamba²  Alessandro Pesaresi²  Rosanna Caliandro² 

[1] Dipartimento di Scienze della Salute, Università degli Studi “Magna Graecia”, Catanzaro, Ital;Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Trieste, Italy;

关键词: donepezil analogues;    acetylcholinesterase;    β-secretase-1;    X-ray Crystallography;    inhibition kinetics;   

DOI  :  10.1080/14756366.2018.1458030

来源: publisher

【 摘 要 】

Acetylcholinesterase inhibitors were introduced for the symptomatic treatment of Alzheimer’s disease (AD). Among the currently approved inhibitors, donepezil (DNP) is one of the most preferred choices in AD therapy. The X-ray crystal structures of Torpedo californica AChE in complex with two novel rigid DNP-like analogs, compounds 1 and 2, have been determined. Kinetic studies indicated that compounds 1 and 2 show a mixed-type inhibition against TcAChE, with Ki values of 11.12 ± 2.88 and 29.86 ± 1.12 nM, respectively. The DNP rigidification results in a likely entropy-enthalpy compensation with solvation effects contributing primarily to AChE binding affinity. Molecular docking evidenced the molecular basis for the binding of compounds 1 and 2 to the active site of β-secretase-1. Overall, these simplified DNP derivatives may represent new structural templates for the design of lead compounds for a more effective therapeutic strategy against AD by foreseeing a dual AChE and BACE-1 inhibitory activity.

【 授权许可】

CC BY