Insights into the molecular basis of acetylcholinesterase inhibition by xanthones: an integrative in silico and in vitro approach

Xanthones from natural and synthetic origins have shown interesting diverse pharmacological activities. This study aims to assess the in silico and in vitro activities of new synthetic xanthones as inhibitors of acetylcholinesterase enzyme (AChE). A series of eight new xanthones were designed and synthesised, using an in house strategy, from a readily available starting material. Their inhibitory activities against AChE were assessed in vitro and presented as IC50 values. The binding mode of these compounds inside AChE was investigated using Auto-Dock 4.2.2. Additionally, molecular dynamics simulation was performed, using GROMACS 5.0.2, to explore the dynamics of the inhibitory mechanism and stability of xanthone 5a within the active site of AChE enzyme. All xanthones showed promising activities when tested in vitro and in silico with xanthone 5a being the most potent in terms of both binding energy (-12.32 kcal/mol) and IC50 (0.20 +/- 0.04 mu M). Molecular dynamics simulation revealed several interesting features responsible for the potency of xanthone 5a as an AChE inhibitor. Furthermore, the calculated Log P of xanthone (5a) was found to be 6.56 suggesting it to be a potential drug candidate for the management of AChE associated diseases such as Alzheimer's disease and myasthenia gravis.