Semi-synthetic studies of 2-substituted huperzine A analogues as acetylcholinesterase inhibitors

Name: Wareepat Tiyabhorn

Organization : Chulabhorn Royal Academy of Science. Chulabhorn Graduate Institute

Name: Pornkanok Pongpamorn

Organization : Chulabhorn Royal Academy of Science. Chulabhorn Graduate Institute

Name: Richard Sessions

Organization : University of Bristol. School of Biochemistry

Name: Somsak Ruchirawat

Organization : Chulabhorn Research Institute. Laboratory of Medicinal Chemistry

Name: Nopporn Thasana

Organization : Chulabhorn Research Institute. Laboratory of Medicinal Chemistry

Email : nopporn@cri.or.th

keyword: huperzine A

LCSH: Acetylcholinesterase

LCSH: Alzheimer disease

Abstract: Huperzine A (HupA), a Lycopodium alkaloid, is known as a potent and reversible inhibitor of acetylcholinesterase (AChE) which shows a therapeutic benefit for Alzheimer’s disease (AD). In this study, HupA, isolated from a club moss Huperzia carinata, was derivatized at C2 position to improve its binding affinity toward AChE. The crystallographic structure of human AChE complexed Hup A revealed that in the vicinity of the pyridone ring at C2 position, there is still space available for introducing designed novel substitutions to increase the binding interactions with amino acids inside the AChE pocket. Over 20 HupA analogues have been designed and studied using BUDE (Bristol University Docking Engine), Amber, and Waterswap Sire. The in silico results led to a number of analogues, modified at C2 position on HupA, that have binding poses nearly similar to the parent molecule, with lower ΔG ligand binding free energies in the range of -37.8 ± 4.7 to -50.8 ± 4.9 kcal mol-1. Nevertheless, to our knowledge, the modification of C2 position of Hup A has not yet been investigated. This work would be useful to attain knowledge and better understanding for quantitative study-activity relationship (QSAR) of 2-substituted HupA analogues.

King Mongkut's University of Technology North Bangkok. Central Library

Address: BANGKOK

Email: library@kmutnb.ac.th

Created: 2018

Modified: 2019-07-22

Issued: 2019-07-11

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BibliograpyCitation : In Prince of Songkla University Faculty of Science. Pure and Applied Chemistry International Conference (PACCON 2018) (pp.NP32-NP37). Songkla : Prince of Songkla University

eng

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