Comparative study of selective in vitro and in silico BACE1 inhibitory potential of glycyrrhizin together with its metabolites, 18a- and 18b-glycyrrhetinic acid, isolated from Hizikia fusiformis

Hizikia fusiformis (Harvey) Okamura is a brownseaweed widely used in Korea and Japan, and it containsdifferent therapeutically active constituents. In the presentstudy, we investigated the activities of glycyrrhizin isolatedfrom H. fusiformis, including its metabolites, 18a- and18b-glycyrrhetinic acid against Alzheimer’s disease (AD)via acetyl and butyrylcholinesterase and b-site amyloidprecursor protein cleaving enzyme 1 (BACE1) inhibition. Among these three compounds, 18b-glycyrrhetinic acid(IC50 = 8.93 ± 0.69 lM) demonstrated two fold potentactivity against BACE1 compared to the positive control,quercetin (IC50 = 20.18 ± 0.79 lM). Additionally, glycyrrhizinwith an IC50 value of 20.12 ± 1.87 lM showedsimilarity to quercetin, while 18a-glycyrrhetinic acidshowed moderate activity (IC50 = 104.35 ± 2.84 lM). Akinetic study revealed that glycyrrhizin and 18b-glycyrrhetinicacid were non-competitive and competitiveinhibitiors of BACE1, demonstrated via Ki values of 16.92and 10.91 lM, respectively. Molecular docking simulationstudies evidently revealed strong binding energy of thesecompounds for BACE1, indicating their high affinity andcapacity for tighter binding to the active site of the enzyme. These data suggest that glycyrrhizin isolated from theedible seaweed, H. fusiformis and its metabolite, 18b-glycyrrhetinicacid demonstrated selective inhibitory activityagainst BACE1 to alleviate AD. KCI Citation Count: 22