Molecular Docking and Design of Novel Heterodimers of Donepezil and Huperzine Fragments as Acetylcholinesterase Inhibitors

To provide hints for the design of new acetylcholinesterase (AChE) inhibitors with higher potency and specificity, the binding modes of novel heterodimers comprised of donepezil and huperzine A fragments with AChE were explored by employing the docking simulations. The results show that the binding mode of S-17b (the most potent inhibitor in Ref. 2, i.e., Bioorg. Med. Chem. 2013, 21, 676-683) is clearly different from that of donepezil, while the binding modes of other heterodimers in Ref. 2 are the same as that of donepezil. In addition, based on the binding mode and structure modification of S-17b, two novel inhibitors (S-17b1 and S-17bb1) with much higher inhibitory potency than S-17b were obtained. Our design strategy was to replace the hupyridone moiety of S-17b with the bulky group, and to replace the dimethoxyindanone moiety of S-17b with more hydrophobic and bulky group with a highly positive charge, which would result in generating potent and selective AChE inhibitors.