Journal:Neuropharmacology:1

Slow-binding inhibitors of acetylcholinesterase of medical interest

Sofya V. Lushchekina and Patrick Masson ^[1]

Molecular Tour
Certain ligands slowly bind to acetylcholinesterase. As a result, there is a slow establishment of enzyme-inhibitor equilibrium characterized by a slow onset of inhibition prior reaching steady state. Three mechanisms account for slow-binding inhibition: a) slow binding rate constant k_on, b) slow ligand induced-fit following a fast binding step, c) slow conformational selection of an enzyme form. The slow equilibrium may be followed by a chemical step. This later that can be irreversible has been observed with certain alkylating agents and substrate transition state analogs. Slow-binding inhibitors present long residence times on target. This results in prolonged pharmacological or toxicological action.

Through several well-known molecules (e.g. huperzine) and new examples (tocopherol, trifluoroacetophenone and a 6-methyluracil alkylammonium derivative), we show that slow-binding inhibitors of acetylcholinesterase are promising drugs for treatment of neurological diseases such as Alzheimer disease and myasthenia gravis. Moreover, they may be of interest for neuroprotection (prophylaxis) against organophosphorus poisoning.

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• Apo-state AChEs (1ea5, 1qid, 1w75, 2j3d, 2va9) are colored in pink.
• Huperzine A (yellow, structure of huperzine B, is added, colored in gold). (+)-Huperzine A/TcAChE PDB ID 1gpk, (-)-huperzine B/TcAChE PDB ID 1gpn; (-)-huperzine A /TcAChE PDB ID 1vot.
• Galantamine and its derivatives (pale cyan, complex of charged analog of galantamine is highlighted with brighter shade of cyan). (-)-Galanthamine/TcAChE PDB ID 1dx6; (-)-galanthamine/TcAChE PDB ID 1qti; bis-acting galanthamine derivatives/TcAChE PDB IDs 1w4l, 1w76, galanthamine with quaternized nitrogen atom/TcAChE PDB ID 1w6r; Npiperidinopropyl-galanthamine/TcAChE PDB ID 3i6m, N-saccharinohexyl-galanthamine/TcAChE PDB ID 3i6z.
• Donepezil and its derivatives (pale green). Donepezil/TcAChE PDB ID 1eve; donepezil-like inhibitor 17/TcAChE PDB ID 5nap, donepezil-like compound 20/TcAChE PDB ID 5nau.

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• Apo-state hAChE (PDB ID 4ey4) is colored in pink.
• Huperzine A (yellow; (-)-huperzine A/hAChE PDB ID 4ey5).
• Galantamine (pale cyan; (-)-galanthamine/hAChE PDB ID 4ey6).
• Donepezil (pale green; donepezil/hAChE PDB ID 4ey7).
• X-ray structure of mouse AChE (structure analogous to human AChE) with C-547 is added in orange (C-547/mAChE PDB ID 5fkj).

References

1. ↑ Lushchekina SV, Masson P. Slow-binding inhibitors of acetylcholinesterase of medical interest. Neuropharmacology. 2020 Jul 23:108236. doi: 10.1016/j.neuropharm.2020.108236. PMID:32712274 doi:http://dx.doi.org/10.1016/j.neuropharm.2020.108236