GALANTAMINE AND DONEPEZIL COMBINATION AS CHOLINESTERASES INHIBITORS IN ALZHEIMER'S DISEASE THERAPY

ADARVEZ-FERESIN C; ZARAGOZA PUCHOL D.; PARRAVICINI O.; GARRO A.; ENRIZ D.; FERESIN GE

Mendoza

Congreso; XL Reunión Científica Anual de la Sociedad de Biología de Cuyo; 2022

Sociedad de Biologia de Cuyo

Alzheimer's disease (AD) is the most common cause of dementia affecting the elderly population. Current drug-based treatments that may temporarily ease symptoms or slow down the progression consist of cholinesterase inhibitors (iChE) designed to increase acetylcholine levels to maintain the cholinergic signal. There are six treatment FDA-approved: iChE including galantamine (GAL), donepezil (DON), and rivastigmine;N-methyl-D-aspartate antagonists, donepezil-memamntine combination therapy; and recently approved monoclonal antibodies (aducanumab). The pharmacological interaction between a combination of drugs results in a synergistic (increases), antagonist (decreases) or indifferent effects. Thise aim of this study aimed was to perform a kinetic analysis study to determine 1- the in vitrointeraction of the GAL (a natural product of Amaryllidaceae) and DON (synthetic drug) combination against AChE and BuChE cholinesterases; and 2- to corroborate these results by a molecular modelling study employing docking techniques, molecular dynamics simulations and QTAIM (Quantum Theory of Atoms in Molecules) studies. The results from the kinetic plots showed that when GAL and DON are combined over a range of concentrations around the IC50, the best inhibition of AChE occurred with the mixture containing the highest concentration of GAL and the lowest of DON. Evidence from Molecular modelling indicated the existence of co-occupancy of the ligands in both enzymes. In the AChE result was important that GAL must first occupy the active site before DON. Moreover, it is important to highlight that in BuChE, the two ligands are easily located due to the larger size of the active site of this enzyme, obtaining six possible poses. On the other hand, from the simulations of the complexes for AChE, three possible poses were shown. The present results may indicate that the combined use of GAL and DON may represent a starting point to reduce the dose and avoid hepatotoxic and gastrointestinal side effects. It also lays the foundation for further studies on the interaction of other compounds isolated from natural sources that inhibit cholinesterase