title: Anti-Alzheimer's disease potential of coumarins from Angelica decursiva and Artemisia capillaris and structure-activity analysis.
abstract: OBJECTIVE
  To use structure-activity analysis to study the anti-Alzheimer's disease (anti-AD) activity of natural coumarins isolated from Angelica decursiva and Artemisia capillaris, along with one purchased coumarin (daphnetin).
  
  
  METHODS
  Umbelliferone, umbelliferone 6-carboxylic acid, scopoletin, isoscopoletin, 7-methoxy coumarin, scoparone, scopolin, and esculetin have been previously isolated; however 2'-isopropyl psoralene was isolated from Angelica decursiva for the first time to evaluate their inhibitory effects against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) enzyme activity. We scrutinized the potentials of coumarins as cholinesterase and BACE1 inhibitors via enzyme kinetics and molecular docking simulation.
  
  
  RESULTS
  Among the test compounds, umbelliferone 6-carboxylic acid, esculetin and daphnetin exhibited potent inhibitory activity against AChE, BChE and BACE1. Both esculetin and daphnetin have a catechol group and exhibit significant anti-AD activity against AChE and BChE. In contrast, presence of a sugar moiety and methoxylation markedly reduced the anti-AD activity of the coumarins investigated in this study. With respect to BACE1 inhibition, umbelliferone 6-carboxylic acid, esculetin and daphnetin contained carboxyl or catechol groups, which significantly contributed to their anti-AD activities. To further investigate these results, we generated a 3D structure of BACE1 using Autodock 4.2 and simulated binding of umbelliferone 6-carboxylic acid, esculetin and daphnetin. Docking simulations showed that different residues of BACE1 interacted with hydroxyl and carboxylic groups, and the binding energies of umbelliferone 6-carboxylic acid, esculetin and daphnetin were negative (-4.58, -6.25 and -6.37 kcal/mol respectively).
  
  
  CONCLUSIONS
  Taken together, our results suggest that umbelliferone 6-carboxylic acid, esculetin and daphnetin have anti-AD effects by inhibiting AChE, BChE and BACE1, which might be useful against AD.
authors.affiliation: Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea.
authors.forename: Md Yousof
authors.initials: MY
authors.lastname: Ali
authors.affiliation: Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea.
authors.forename: Susoma
authors.initials: S
authors.lastname: Jannat
authors.affiliation: Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju 561-756, Republic of Korea. Electronic address: jungha@jbnu.ac.kr.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Jung
authors.affiliation: Angiogenesis & Chinese Medicine Laboratory, Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Ran Joo
authors.initials: RJ
authors.lastname: Choi
authors.affiliation: Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea.
authors.forename: Anupom
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea. Electronic address: choijs@pknu.ac.kr.
authors.forename: Jae Sue
authors.initials: JS
authors.lastname: Choi
keywords: BACE1; Cholinesterase; Coumarins; Daphnetin; Esculetin; Umbelliferone 6-carboxylic acid