In:
Scientific Reports, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-12-10)
Abstract:
Cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have been attracted as candidate treatments for Alzheimer's disease (AD). Fifteen khellactone-type coumarins from the roots of Peucedanum japonicum Thunberg were tested for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and MAO inhibitory activities. Compound 3′-angeloyl-4′-(2-methylbutyryl)khellactone ( PJ13 ) most potently inhibited AChE (IC 50 = 9.28 µM), followed by 3′-isovaleryl-4′-(2-methylbutyroyl)khellactone ( PJ15 ) (IC 50 = 10.0 μM). Compound senecioyl-4′-angeloyl-khellactone ( PJ5 ) most potently inhibited BChE (IC 50 = 7.22 μM) and had the highest selectivity index ( 〉 5.54), followed by 3′-senecioyl-4′-(2-methylbutyryl)khellactone ( PJ10 ) and 3′,4′-disenecioylkhellactone ( PJ4 ) (IC 50 = 10.2 and 10.7 μM, respectively). Compounds PJ13 , PJ15 , and PJ5 showed reversible and mixed-types of inhibition with K i values of 5.98, 10.4 (for AChE), and 4.16 µM (for BChE), respectively. However, all 15 compounds weakly inhibited MAO-A and MAO-B. Molecular docking simulation revealed that PJ13 had a higher binding affinity (− 9.3 kcal/mol) with AChE than PJ15 (− 7.8 kcal/mol) or PJ5 (− 5.4 kcal/mol), due to the formation of a hydrogen bond with Tyr121 (distance: 2.52 Å). On the other hand, the binding affinity of PJ5 (− 10.0 kcal/mol) with BChE was higher than for PJ13 (− 7.7 kcal/mol) or PJ15 (− 8.1 kcal/mol), due to the formation of a hydrogen bond with Ser198 (distance: 2.05 Å). These results suggest that PJ13 and PJ5 are potential reversible selective inhibitors of AChE and BChE, respectively, for the treatment of AD.
Type of Medium:
Online Resource
ISSN:
2045-2322
DOI:
10.1038/s41598-020-78782-5
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2020
detail.hit.zdb_id:
2615211-3
