Theoretical Investigation of Natural and Synthetic Cholinesterase Inhibitors for Alzheimer’s Disease Treatment

Abstract

In Alzheimer’s disease (AD), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) represent important enzymatic targets, with inhibition achieved using either natural products or synthetic compounds. Passiflora incarnata provides natural bioactive molecules, mainly flavonoids (apigenin, luteolin, myricetin, orientin, quercetin, kaempferol, vitexin, isovitexin, isoorientin) and alkaloids (harman, harmine, harmol, harmaline, harmalol, 8-hydroxyharmine, harmine N-oxide). Prominent examples of synthetic inhibitors employed in clinical practice include donepezil, rivastigmine, galantamine, and tacrine.

To advance the design of next-generation inhibitors, molecular docking simulations were employed to screen for ligands with optimal interaction energies and to elucidate their binding affinities for each target enzyme. The analysis of natural products highlighted flavonoids as the most promising class, with isovitexin and orientin revealing the most robust binding profiles for AChE and BuChE. In parallel, donepezil demonstrated the highest affinity among the synthetic comparators.

These data illuminate the therapeutic viability of diverse chemical scaffolds in mitigating AD-associated enzyme activity, offering a valuable foundation for the development of optimized pharmacological treatments.