Kinetics and molecular docking studies of loganin, morroniside and 7-O-galloyl-D-sedoheptulose derived from Corni fructus as cholinesterase and β-secretase 1 inhibitors.
We evaluated the major active components isolated from Corni Fructus: loganin, morroniside, and 7-O-galloyl-D-sedoheptulose as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) for use in Alzheimer's disease treatment. These compounds exhibited predominant cholinesterase (ChEs) inhibitory effects with IC50 values of 0.33, 3.95, and 10.50 ± 1.16 µM, respectively, for AChE, and 33.02, 37.78, and 87.94 ± 4.66 µM, respectively, for BChE. Kinetics studies revealed that loganin and 7-O-galloyl-D-sedoheptulose inhibited AChE with characteristics typical of mixed inhibitors, while morroniside was found to be a noncompetitive inhibitor against AChE and also exerted mixed BChE inhibitory activities. For BACE1, loganin showed noncompetitive type inhibitory effects, while morroniside and 7-O-galloyl-D-sedoheptulose were found to be mixed inhibitors. Furthermore, these compounds exhibited dose-dependent inhibitory activity with ONOO(-)-mediated protein tyrosine nitration. Molecular docking simulation of these compounds demonstrated negative binding energies for ChEs, and BACE1, indicating high affinity and tighter binding capacity for the active site of the enzyme. Loganin was the most potent inhibitor against both ChEs and BACE1. The data suggest that these compounds together can act as a triple inhibitor of AChE, BChE, and BACE1, providing a preventive and therapeutic strategy for Alzheimer's disease treatment.
Department of Food and Life Science, Pukyong National University, Busan, 608-737, Republic of Korea.
Himanshu Kumar
HK
Bhakta
College of Pharmacy, Catholic University of Daegu, Gyeongsan, 712-702, Republic of Korea.
Chan Hum
CH
Park
Graduate School of Science and Engineering for Research, University of Toyama, Toyama, 930-8555, Japan.
Takako
T
Yokozawa
College of Pharmacy, Catholic University of Daegu, Gyeongsan, 712-702, Republic of Korea.
Byung-Sun
BS
Min
Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju, 561-756, Republic of Korea. jungha@jbnu.ac.kr.
Hyun Ah
HA
Jung
Department of Food and Life Science, Pukyong National University, Busan, 608-737, Republic of Korea. choijs@pknu.ac.kr.
Jae Sue
JS
Choi
D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D029768:Cornus / Q000737:chemistry*; D055808:Drug Discovery / Q000379:methods*; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D006539:Heptoses / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D039823:Iridoids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D007700:Kinetics; D062105:Molecular Docking Simulation; D011485:Protein Binding
C540464:7-O-galloyl-D-sedoheptulose; D002800:Cholinesterase Inhibitors; D006027:Glycosides; D006539:Heptoses; D039823:Iridoids; C488401:morroniside; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C059516:loganin
7-O-galloyl-D-sedoheptulose; Alzheimer’s disease; BACE1; Cholinesterase; Loganin; Peroxynitrite-mediated protein tyrosine nitration