In order to design novel tacrine-huperzine A hybrid (Huperzine X) derivatives, a new practical proposal was built to calculate binding free energy. The method assumed that the free energy of binding was cast simply as a linear combination of three descriptors: interaction energy between inhibitors and protein, the difference in the absolute conformation free energy of protein between the bound and unbound states, and the free energy increase of inhibitors from the stabilized conformation to activity conformation. For the total of 14 huperzine X derivatives, the result obtained from the method was found to correlate well to the inhibitory activity IC₅₀ for acetylocholinesterases with the Spearman's correlation coefficient r_s＝0.85.

Key words: binding free energy, huperzine X, acetylocholinesterase, molecular dynamics