BACE1 molecular docking and anti-Alzheimer's disease activities of ginsenosides.
BACKGROUND
Ginsenosides are natural product steroid glycosides and triterpene saponins obtained from the Panax species. Panax ginseng has been widely used as a traditional Chinese medicine (TCM) for around a thousand years, especially in East Asian countries. Ginseng, the root and rhizome of the most popular species P. ginseng, used as tonic, prophylactic agent and restorative. In TCM, ginseng is highly valued herb and has been applied to a variety of pathological conditions and illnesses such as hypodynamia, anorexia, shortness of breath, palpitation, insomnia, impotence, hemorrhage and diabetes.


OBJECTIVE
The basic aim of this study was to evaluate the anti-Alzheimer's disease activities of selected ginsenosides (Rb1, Rb2, Rc, Re, Rg1, and Rg3) according to peroxynitrite (ONOO(‒)) scavenging activity and inhibitory activity of ONOO(-)-mediated nitrotyrosine formation as a measure of changes in oxidative stress. In addition, molecular docking simulation studies were performed to predict binding energies of the ginsenosides with β-site amyloid precursor protein cleaving enzyme 1 (BACE1, β-secretase) and identify the interacting residues.


METHODS
In vitro cholinesterase enzyme assays by using acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE1 were performed. In vitro authentic peroxynitrite scavenging activity and inhibitory activity against ONOO(-)-mediated nitrotyrosine formation were also performed. Molecular docking simulation studies were performed with Autodock Vina software and Discovery studio 4.1.


RESULTS
In vitro enzyme assays demonstrated that ginsenosides have significant inhibitory potential against AChE, BChE, and BACE1, as well as ONOO(-) and nitrotyrosine formation. Most importantly, significant AChE inhibitory activities were observed for Re; BChE for Rg3; and BACE1 for Rc, with IC50 values of 29.86±3.20, 16.80±0.36, and 59.81±2.74μg/mL, respectively. Among the tested ginsenosides, Rb1 exhibited a higher scavenging activity against ONOO(-) with an IC50 value of 27.86±1.34μg/mL, while Rc and Rg3 exhibited impressive inhibitory activity against the formation of nitrotyrosine. In addition, molecular docking studies revealed potential BACE1 inhibitory activity of ginsenosides, especially Rb1 and Rb2, which exhibited good binding affinities towards BACE1, with docking scores of -10kcal/mol.


CONCLUSIONS
The findings of the present study suggest the potential of ginsenosides (Rb1, Rb2, Rc, Re, Rg1, and Rg3) for use in the development of therapeutic or preventive agents for Alzheimer's disease, especially through inhibition of AChE, BChE and BACE1 activities, as well as scavenging of ONOO(-) and inhibition of nitrotyrosine formation.
Angiogenesis & Chinese Medicine Laboratory, Department of Pharmacology, University of Cambridge, Cambridge, UK.
Ran Joo
RJ
Choi
Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea.
Anupom
A
Roy
Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea.
Hee Jin
HJ
Jung
Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea.
Md Yousof
MY
Ali
College of Pharmacy, Catholic University of Daegu, Gyeongbuk 712-702, Republic of Korea.
Byung-Sun
BS
Min
College of Pharmacy, Catholic University of Daegu, Gyeongbuk 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
Angiogenesis & Chinese Medicine Laboratory, Department of Pharmacology, University of Cambridge, Cambridge, UK.
Tai-Ping
TP
Fan
Department of Food and Life Science, Pukyong National University, Busan 608-737, Republic of Korea. Electronic address: choijs@pknu.ac.kr.
Jae Sue
JS
Choi
Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju 561-756, Republic of Korea. Electronic address: jungha@jbnu.ac.kr.
Hyun Ah
HA
Jung
D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D036145:Ginsenosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D002800:Cholinesterase Inhibitors; D036145:Ginsenosides; D011480:Protease Inhibitors; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
Anti-Alzheimer's disease; BACE1; Cholinesterase; Ginsenosides; Molecular docking simulation