Acetylcholinesterase(AChE)and butyrylcholinesterase(BChE)are highly homologous proteins and play important roles in the cholinergic nervous system. In current work,we investigate the bioactivity and selectivity of the pyridonepezils to AChE/BChE. The binding interactions between the two inhibitors and AChE/BChE are examined based on the MM-PBSA method. The results demonstrate that the van der Waals interactions have the largest contributions to the binding free energy,and the pyridonepezil exhibits higher bioactivity and selectivity to AChE/BChE compared to donepezil. The rank of calculated binding free energies is in good agreement with experimental inhibiting constants of the two inhibitors.