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.

. Huperzine A1 (yellow, structure of huperzine B, is added, colored with brighter shade of yellow); galantamine and its derivatives2 (pale cyan, complex of charged analog of galantamine is highlighted with brighter shade of cyan), donepezil and its derivatives3 (pale green). Apo-state AChEs4 are colored in pink.

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