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

doi:10.1021/acsomega.1c02875

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

ACS Omega. 2021 Jul 26;6(30):19924-19939. doi: 10.1021/acsomega.1c02875. eCollection 2021 Aug 3.

Authors

Affiliations

¹ Program in Chemical Sciences, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok 10210, Thailand.
² School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom.
³ Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Bangkok 10210, Thailand.
⁴ The Center of Excellence on Environmental Health and Toxicology, Commission on Higher Education, Ministry of Education, Bangkok 10400, Thailand.

Abstract

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.