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

HUANG Chu-Sheng TU Wen-Tong LUO Min SHI Jian-Cheng

Citation:  HUANG Chu-Sheng, TU Wen-Tong, LUO Min, SHI Jian-Cheng. Molecular Docking and Design of Novel Heterodimers of Donepezil and Huperzine Fragments as Acetylcholinesterase Inhibitors[J]. Chinese Journal of Structural Chemistry, 2016, 35(6): 839-848. doi: 10.14102/j.cnki.0254-5861.2011-0733 shu

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

    通讯作者: SHI Jian-Cheng,
摘要: 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.

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