The binding of Tacrine derivatives to Acetylcholinesterase is examined to evaluate the viability of a practical method calculating absolute binding free energy based on the finite difference thermodynamic integration. The method assumes that ΔG b i n d is given by the difference between the absolute free energy of an inhibitor in protein environment, (ΔG i n h ) p r o t e i n , and that in water environment, (ΔG i n h ) w a t e r . The results obtained from the method were found to correlate well with the experimental active data, Spearman's correlation coefficient, r s =0.90. Moreover, using the CVFF force field found in the commercial package Discover without any special parameters against a set of experimental binding data, the method can expediently and qualitatively rank affinity order of the compounds.