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

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 K_i 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.

Keywords:

• donepezil analogues
• acetylcholinesterase
• β-secretase-1
• X-ray Crystallography
• inhibition kinetics

Acknowledgements

The authors thank the staff of the XRD-1 beamline at Elettra-Sincrotrone Trieste S.C.p.A., Trieste, Italy, for assistance during data collection and are most grateful to the late Dr. Gregory E. Garcia, Research Division, U.S. Army Medical Research Institute of Chemical Defense (Aberdeen Proving Ground, MD, USA) for providing us with purified TcAChE used for the structural study.

Disclosure statement

The authors report no declaration of interest.

Additional information

Funding

Nutramed SCaRL, actuator of the Project PON03PE_00078_1 and PON03PE_00078_1/F1, is acknowledged for the financial support.