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PDBsum entry 5nap
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References listed in PDB file
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Key reference
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Title
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Kinetic and structural studies on the interactions of torpedo californica acetylcholinesterase with two donepezil-Like rigid analogues.
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Authors
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R.Caliandro,
A.Pesaresi,
L.Cariati,
A.Procopio,
M.Oliverio,
D.Lamba.
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Ref.
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J Enzyme Inhib Med Chem, 2018,
33,
794-803.
[DOI no: ]
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PubMed id
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Abstract
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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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