Is possible the co-occupancy of galantamine and donepezil at the AchE and BuChE binding sites? In silico study of the dual interaction

ADARVEZ FERESIN, CAMILA; GARRO, A.D.; PARRAVICINI, O.; FRIGINI, EZEQUIEL N.; ENRIZ, RICARDO D.

Córdoba

Congreso; LI Reunión Anual de la Sociedad Argentina de Biofísica; 2023

IIByT- CONICET ? UNC

Alzheimer's disease (AD) is the most common form of dementia in the ageing population.The current palliative treatment consists of using cholinesterase inhibitors (ChEI) toincrease neurotransmitters levels. The aim of this study was to evaluate the inhibitoryeffect of the combined use of Galantamine (GAL) and Donepezil (DON), two well-knownChEIs, against AChE and BChE throughout an in silico study.The features of GAL and DON make them suitable candidates for a Durg Combination (DC)strategy, since they interact in different regions of the cholinesteres’ actives sites. Thus, itis plausible to expect a cooperative effect between these ChEIs. Some authors reportedthe efficacy of dual-drugs combination to inhibit human AChE. However, a similar studytargeting butyrylcholinesterase (BChE) has not been described.Analyses were carried out for GAL and DON individually and combined. Molecularmodelling studies were carried out by using combined techniques such as dockinganalysis, molecular dynamics simulation, and QTAIM (Quantum theory of atoms inmolecules) calculations. For the GAL and DON combination study through the Molecular Modelling Analysis, theexistence of co-occupancy in both enzymes was observed. For AChE, the bestarrangement for these two drugs in the active site occurs when GAL occupies the activesite before DON. For BChE, the two ligands are easily positioned due to the larger size ofthe active site obtaining six possible poses. To the best of our knowledge, this study represents the first report showing the effect ofdual-drug combinations DON and GAL in silico to inhibit BChE, and displays theimportance of analyzing at molecular level the behavior of different ligands when co-occupancy of the active site is possible. These dual drug cholinesterase Inhibitorscombinations (GAL and DON) might be a possible therapy with improved efficacy,reduced doses, minor side effects, and high level of the neurotransmitter in the synapticspace for the AD treatment.