Inhibitory effect of galantamine and donepezil combination against cholinesterase: An in silico and in vitro study

ADARVEZ FERESIN, CAMILA WADIA; PIÑEIRO, MAURICIO; ORTIZ, JAVIER E.; PARRAVICINI, OSCAR; ENRIZ, DANIEL; GARRO, ADRIANA D.; FERESIN, GABRIELA E.

Archiv der Pharmazie

John Wiley and Sons Inc

Lugar: Nueva Jersey; Año: 2023 vol. 357 p. 1 - 13

This study aimed to evaluate the in silico and in vitro inhibitory effect of the combineduse of galantamine (GAL) and donepezil (DON) against acetylcholinesterase andbutyrylcholinesterase (BuChE) enzymes. In silico and in vitro cholinesterase analysiswere carried out for GAL and DON alone and combined. Molecular modeling studieswere carried out (docking analysis, molecular dynamics simulation, and quantum theoryof atoms in molecules). Cholinesterase´s inhibitory activities by modified Ellman´smethod and the drug combination effect using the Chou–Talalay method were assayed.GAL/DON combination showed the co‐occupancy of the ligands in both enzymesthrough in silico studies. Regarding in vitro BuChE inhibition analyses, three of fivecombinations showed an interaction between GAL and DON at the threshold ofadditive affect (0.9 < CI < 1.1), with a tendency toward a synergistic effect for higherconcentrations. This is the first report showing the efficacy of the GAL/DONcombinations inhibiting BuChE, showing the importance of analyzing the behavior ofdifferent ligands when co‐occupancy into the active site is possible. These combinationsmight be a possible therapy to improved efficacy, reduced doses, minor side effects, andhigh levels of the neurotransmitter in the synaptic space for Alzheimer´s disease.