Molecular docking and molecular dynamics simulation approaches for identifying new lead compounds as potential AChE inhibitors

Abstract

To provide hints for the design of novel acetylcholinesterase (AChE) inhibitors with higher potency and specificity, the binding modes of the (RS, S)-17b and (RS, R)-17b enantiomers on AChE were chosen to investigate by molecular docking and molecular dynamics simulation. The results show that the binding modes of (RS, S)-17b and (RS, R)-17b are clearly different from each other. In particular, the (RS, S)-17b and (RS, R)-17b enantiomers tend to be planar and bend conformations to interact with AChE, respectively. Furthermore, based on the binding mode on AChE and structure modification of (RS, S)-17b, two novel inhibitors (1 and 2) with higher inhibitory activity were designed. Our design strategy suggests that the number of N and O atoms should be increased, the 5, 6-dimethoxy should be transformed into ring and the indanone moiety should be ring-opening, which would result in generating potent and selective AChE inhibitors.