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

Aim: 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. Methods & results: 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 IC50 of less than 100 μM. Among these five compounds, a new molecule, 970180, presented the most potency against BChE, with an IC50 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 970180 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. Conclusion: 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.