Kinetic and structural studies on the interactions of Torpedo californica acetylcholinesterase with two donepezil-like rigid analogues |
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Authors: | Rosanna Caliandro Alessandro Pesaresi Luca Cariati Antonio Procopio Manuela Oliverio |
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Affiliation: | 1. Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Trieste, Italy;2. Dipartimento di Scienze della Salute, Università degli Studi “Magna Graecia”, Catanzaro, Italy |
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Abstract: | 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. |
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Keywords: | donepezil analogues acetylcholinesterase β-secretase-1 X-ray Crystallography inhibition kinetics |
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