Discovery, biological evaluation and molecular dynamic simulations of butyrylcholinesterase inhibitors through structure-based pharmacophore virtual screening.

Butyrylcholinesterase (BChE) is a crucial therapeutic target because it is associated with multiple pathological elements of Alzheimer's disease (AD). An integrated computational strategy was employed to exploit effective BChE inhibitors. Ten compounds derived from the Enamine database by structure-based pharmacophore virtual screening were further evaluated for biological activity; out of the ten, only five had an IC of less than 100 μM. Among these five compounds, a new molecule, , presented the most potency against BChE, with an IC of 4.24 ± 0.16 μM, and acted as a mixed-type inhibitor. Molecular dynamic simulations and absorption, distribution, metabolism and excretion prediction further confirmed its high potential as a good candidate of BChE inhibitor. Furthermore, cytotoxicity of molecule was not observed at concentrations up to 50 μM, and the molecule also showed a prominent neuroprotective effect compared with tacrine at 25 and 50 μM. This study provides an effective structure-based pharmacophore virtual screening method to discover BChE inhibitors and provide new choices for the development of BChE inhibitors, which may be beneficial for AD patients.