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Arylbenzofurans from the Root Bark of Morus alba as Triple Inhibitors of Cholinesterase, ?-Site Amyloid Precursor Protein Cleaving Enzyme 1, and Glycogen Synthase Kinase-3?: Relevance to Alzheimer's Disease.

ABSTRACT: Cholinesterase, ?-site amyloid precursor protein cleaving enzyme 1 (BACE1), and glycogen synthase kinase-3? (GSK-3?) are the three main enzymes responsible for the early onset of Alzheimer's disease (AD). The main aim of the present study was to delineate and accentuate the triple-inhibitory potential of arylbenzofurans from Morus alba against these enzymes. Overall, the enzyme inhibition assays demonstrated the prominence of mulberrofuran D2 as an inhibitor of AChE, BChE, BACE1, and GSK-3? enzymes with IC50 values of 4.61, 1.51, 0.73, and 6.36 ?M, respectively. Enzyme kinetics revealed different modes of inhibition, and in silico modeling suggested that mulberrofuran D2 inhibited these enzymes with low binding energy through hydrophilic, hydrophobic, and ?-cation interactions in the active site cavities. Similarly, in A?-aggregation assays, mulberrofuran D2 inhibited self-induced and AChE-induced A? aggregation in a concentration-dependent manner that was superior to reference drugs. These results suggest that arylbenzofurans from M. alba, especially mulberrofuran D2, are triple inhibitors of cholinesterase, BACE1, and GSK-3? and may represent a novel class of anti-AD drugs.

SUBMITTER: Paudel P

PROVIDER: S-EPMC6649263 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Arylbenzofurans from the Root Bark of <i>Morus alba</i> as Triple Inhibitors of Cholinesterase, β-Site Amyloid Precursor Protein Cleaving Enzyme 1, and Glycogen Synthase Kinase-3β: Relevance to Alzheimer's Disease.

Paudel Pradeep P Seong Su Hui SH Zhou Yajuan Y Ha Manh Tuan MT Min Byung Sun BS Jung Hyun Ah HA Choi Jae Sue JS

ACS omega 20190404 4

Cholinesterase, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), and glycogen synthase kinase-3β (GSK-3β) are the three main enzymes responsible for the early onset of Alzheimer's disease (AD). The main aim of the present study was to delineate and accentuate the triple-inhibitory potential of arylbenzofurans from <i>Morus alba</i> against these enzymes. Overall, the enzyme inhibition assays demonstrated the prominence of mulberrofuran D2 as an inhibitor of AChE, BChE, BACE1, and GSK- ...[more]

PMID: 31459768

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Project description:Among the 2-arylbenzofuran derivatives isolated from Morus alba, the farnesylated 2-arylbenzofuran is a rarer constituent. The derivative has been reported to exert anti-obesity effect; however, its inhibitory effect on protein tyrosine phosphatase 1B (PTP1B) has not been investigated. In the previous study, the presence of the farnesyl group in the structure of 2-arylbenzofurans was found to have positive influences on their pancreatic lipase inhibitory activity. In the present study, we have confirmed the authenticity of the notation based on the PTP1B inhibitory activity of farnesylated 2-arylbenzofurans. Specifically, two farnesylated 2-arylbenzofurans [morusalfurans B (2) and C (3)] showed strong inhibitory effects on PTP1B with IC50 values of 8.92 and 7.26 µM, respectively, which was significantly higher than that of the positive controls [sodium orthovanadate (IC50?=?15.10 µM) and ursolic acid (IC50?=?11.34 µM)]. Besides, two 2-arylbenzofurans [morusalfurans A (1) and F (6)], one flavonoid [morusalnol B (9)], and one geranylated stilbene [morusibene A (11)] exhibited PTP1B inhibition with IC50 values ranging from 11.02 to 26.56 µM. Kinetic studies revealed compounds 2, 3, 6, and 11 as mixed type PTP1B inhibitors, while 1 and 9 are known as noncompetitive. Molecular docking simulations demonstrated that these active compounds can bind with the respective catalytic or/and allosteric sites of PTP1B with negative binding energies and the results are in accordance with that of the kinetic studies. To the best of our knowledge, this is the first time, the PTP1B inhibitory activity of eleven compounds (1-11), as well as the mechanism of action underlying the effects on PTP1B enzyme of the active compounds, were investigated. In vitro and in silico results suggest that the farnesylated 2-arylbenzofurans from M. alba may potentially be utilized as an effective treatment therapy for type 2 diabetes mellitus and its associated complications.

Dataset Information

Arylbenzofurans from the Root Bark of Morus alba as Triple Inhibitors of Cholinesterase, ?-Site Amyloid Precursor Protein Cleaving Enzyme 1, and Glycogen Synthase Kinase-3?: Relevance to Alzheimer's Disease.

Publications

Arylbenzofurans from the Root Bark of <i>Morus alba</i> as Triple Inhibitors of Cholinesterase, β-Site Amyloid Precursor Protein Cleaving Enzyme 1, and Glycogen Synthase Kinase-3β: Relevance to Alzheimer's Disease.

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