Identification par criblage virtuel et analyses biologiques de nouveaux inhibiteurs de l’acétylcholinestérase pour le traitement de la maladie d’Alzheimer.

Abstract

Acetylcholinesterase (AChE) is currently the most favorable target for the symptomatic treatment and reduction of Alzheimer’s disease (AD). In this work, a new structure-based virtual screening strategy was used in order to identify, among 14307 compounds of Institut Curie-CNRS chemical library, new potent AChE inhibitors. The strategy undertaken in this work consisted of the use of several docking programs in SBVS calculations followed by the application of a consensus method (vSDC) and a scrupulous visual analysis. It allowed us to obtain a high degree of success, with a yield of almost 86%, since 12 hits were identified among only 14 molecules tested in vitro. Still more remarkably, 6 of these hits were more active than galantamine, the reference inhibitor. These hits were predicted to have good ADMET properties. Finally, the in vivo study of cytotoxicity undertaken on Artemia salina larvae showed, in particular, through the evaluation of the LC50 / IC50 ratio that the six hits have a greater inhibitory activity than their toxic effect, which can thus be used as starting structures for the optimization and design of new AD drug candidates.