In Silico-Guided Rational Drug Design and Semi-synthesis of C(2)-Functionalized Huperzine A Derivatives as Acetylcholinesterase Inhibitors

Shisanupong Anukanon, Pornkanok Pongpamorn, Wareepat Tiyabhorn, Jaruwan Chatwichien, Worawat Niwetmarin, Richard B Sessions, Somsak Ruchirawat, Nopporn Thasana*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

4 Citations (Scopus)
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Huperzine A (1, Hup A), a lycodine-type Lycopodium alkaloid isolated from Thai clubmosses Huperzia squarrosa (G. Forst.) Trevis., H. carinata (Desv. ex. Poir.) Trevis., H. phlegmaria (L.), and Phlegmariurus nummulariifolius (Blume) Chambers (Lycopodiaceae), exerts inhibitory activity on acetylcholinesterase, a known target for Alzheimer's disease therapy. This study investigated the structure-activity relationship of C(2)-functionalized and O- or N-methyl-substituted huperzine A derivatives. In silico-guided screening was performed to search for potential active compounds. Molecular docking analysis suggested that substitution at the C(2) position of Hup A with small functional groups could enhance binding affinity with AChE. Consequently, 12 C(2)-functionalized and four O- or N-methyl-substituted compounds were semi-synthesized and evaluated for their eeAChE and eqBChE inhibitory activities. The result showed that 2-methoxyhuperzine A (10) displayed moderate to high eeAChE inhibitory potency (IC50 = 0.16 μM) with the best selectivity over eqBChE (selectivity index = 3633). Notably, this work showed a case of which computational analysis could be utilized as a tool to rationally screen and design promising drug molecules, getting rid of impotent molecules before going more deeply on labor-intensive and time-consuming drug discovery and development processes.

Original languageEnglish
Pages (from-to)19924-19939
Number of pages16
JournalACS Omega
Issue number30
Early online date26 Jul 2021
Publication statusPublished - 3 Aug 2021

Bibliographical note

Funding Information:
This work was partially supported by the Thailand Research Fund (BRG6080013 for N.T.), Thailand Science Research and Innovation Grant number FEB640035 Project code 50184 for Chulabhorn Royal Academy. Support from the Center of Excellence on Environmental Health and Toxicology, Science & Technology Postgraduate Education and Research Development Office (PERDO), Ministry of Education is also gratefully acknowledged. The authors thank Prof. Timothy C. Gallagher, University of Bristol, UK, for valuable comments on the manuscript.

Funding Information:
This research project was supported by the Center of Excellence on Environmental Health and Toxicology (EHT), the Thailand Research Fund, and Thailand Science Research and Innovation.

Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.


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