Su Hui Seong

Protein tyrosine phosphatase 1B and α-glucosidase inhibitory activities of Pueraria lobata root and its constituents

ETHNOPHARMACOLOGICAL RELEVANCE Pueraria lobata root was used to treat wasting-thirst regarded as diabetes mellitus and was included in the composition of Okcheonsan, which is prescribed for thirst-waste in traditional Chinese medicine. AIM OF THE STUDY The objective of this study was to evaluate the anti-diabetic potential of the root of Pueraria lobata and its constituents via protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase inhibitory activities. MATERIALS AND METHODS In this study, anti-diabetic activities of the 70% ethanolic (EtOH) extract from P. lobata roots and its solvent soluble fractions with the isolated compounds were investigated by evaluating in vitro PTP1B and α-glucosidase inhibitory activities. We also examined the potentials of active compounds as PTP1B and α-glucosidase inhibitors via enzyme kinetics and in silico molecular docking simulation between the enzymes and active compounds. RESULTS Triterpenoids lupeol and lupenone were potent PTP1B inhibitors with IC50 values of 38.89±0.17 and 15.11±1.23μM. Kinetic study using the Lineweaver-Burk and Dixon plots demonstrated that these compounds showed a noncompetitive-type inhibition against PTP1B with respective Ki values of 13.88μM and 21.24μM. In addition, molecular docking simulation showed lupeol and lupenone has negative binding energy values of -8.03 and -8.56kcal/mol. Considering the α-glucosidase inhibitory potential, daidzein, genistein, and calycosin exhibited the most potent α-glucosidase inhibition with IC50 values of 8.58±0.94, 2.37±0.52 and 6.84±1.58μM, respectively. Kinetic study demonstrated that these 3 compounds showed a noncompetitive-type inhibition against α-glucosidase with respective Ki values of 17.64μM, 5.03μM and 13.83μM. Moreover, molecular docking simulation showed daidzein, genistein and calycosin has more lower binding energy (-7.16kcal/mol, -7.42kcal/mol and -7.31kcal/mol) with higher binding affinity and tight binding capacity in the molecular docking studies than standard ligand α-D-glucose (-6.74kcal/mol). CONCLUSION Our results of the present study clearly demonstrate the potential of P. lobata extract and its constituents to inhibit PTP1B and α-glucosidase, contributing to the development of therapeutic or preventive agents that can be used in the treatment of diabetes.

BACE1 inhibitory activity and molecular docking analysis of meroterpenoids from Sargassum serratifolium

A wide range of pharmacological properties of Sargassum spp. extracts and isolated components have been recognized. Although individual meroterpenoids of Sargassum species have been reported to possess strong activity against Alzheimers disease (AD), the active compounds of Sargassum serratifolium have not been fully explored. Therefore, we evaluated the anti-AD activity of S. serratifolium extract through enzyme inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1). Three meroterpenoids (sargahydroquinoic acid (1), sargachromenol (2) and sargaquinoic acid (3)) were isolated from S. serratifolium. These compounds showed moderate AChE inhibitory activity, but exhibited potent inhibitory activity against BChE and BACE1 (15.1, 9.4, and 10.4µM for BChE; 4.3, 6.9, and 12.5µM for BACE1, respectively). Kinetic study and molecular docking simulation of these compounds demonstrated that 1 and 3 interacted with both catalytic aspartyl residues and allosteric sites of BACE1, whereas 2 interacted with the allosteric site of BACE1. The results of the present study demonstrate that meroterpenoids from S. serratifolium might be beneficial in the treatment of AD.

Anti-Alzheimer’s disease activity of compounds from the root bark of Morus alba L.

The inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays important roles in prevention and treatment of Alzheimer’s disease (AD). Among the individual parts of Morus alba L. including root bark, branches, leaves, and fruits, the root bark showed the most potent enzyme inhibitory activities. Therefore, the aim of this study was to evaluate the anti-AD activity of the M. alba root bark and its isolate compounds, including mulberrofuran G (1), albanol B (2), and kuwanon G (3) via inhibition of AChE, BChE, and BACE1. Compounds 1 and 2 showed strong AChE- and BChE-inhibitory activities; 1–3 showed significant BACE1 inhibitory activity. Based on the kinetic study with AChE and BChE, 2 and 3 showed noncompetitive-type inhibition; 1 showed mixed-type inhibition. Moreover, 1–3 showed mixed-type inhibition against BACE1. The molecular docking simulations of 1–3 demonstrated negative binding energies, indicating a high affinity to AChE and BACE1. The hydroxyl group of 1–3 formed hydrogen bond with the amino acid residues located at AChE and BACE1. Consequently, these results indicate that the root bark of M. alba and its active compounds might be promising candidates for preventive and therapeutic agents for AD.

Ellagitannin and flavonoid constituents from Agrimonia pilosa Ledeb. with their protein tyrosine phosphatase and acetylcholinesterase inhibitory activities

A new ellagitannin, agritannin (1), a new flavone glycoside, agriflavone (2), and another flavone glycoside with spectroscopic data reported for the first time, kaempferol-3-O-[(S)-3-hydroxy-3-methylglutaryl (1→6)]-β-d-glucoside (3), along with 16 known compounds were isolated from the aerial parts of Agrimonia pilosa Ledeb. These compounds were evaluated for PTP1B inhibitory activity. Among them, compounds 9 and 18 displayed potential inhibitory activity against PTP1B with IC50 values of 7.14±1.75 and 7.73±0.24μM, respectively. In addition, compound 1 showed significant inhibitory effect with an IC50 value of 17.03±0.09μM. Furthermore, these compounds were tested in AChE inhibitory assays. Most of them were found to have moderate inhibitory effects, with IC50 values ranging from 60.20±1.09 to 92.85±1.12μM. Except compounds 3, 8, and 18 were inactive.

Structure-related protein tyrosine phosphatase 1B inhibition by naringenin derivatives

Naturally occurring flavonoids co-exist as glycoside conjugates, which dominate aglycones in their content. To unveil the structure-activity relationship of a naturally occurring flavonoid, we investigated the effects of the glycosylation of naringenin on the inhibition of enzyme systems related to diabetes (protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase) and on glucose uptake in the insulin-resistant state. Among the tested naringenin derivatives, prunin, a single-glucose-containing flavanone glycoside, potently inhibited PTP1B with an IC50 value of 17.5±2.6µM. Naringenin, which lacks a sugar molecule, was the weakest inhibitor compared to the reference compound, ursolic acid (IC50: 5.4±0.30µM). In addition, prunin significantly enhanced glucose uptake in a dose-dependent manner in insulin-resistant HepG2 cells. Regarding the inhibition of α-glucosidase, naringenin exhibited more potent inhibitory activity (IC50: 10.6±0.49µM) than its glycosylated forms and the reference inhibitor, acarbose (IC50: 178.0±0.27µM). Among the glycosides, only prunin (IC50: 106.5±4.1µM) was more potent than the positive control. A molecular docking study revealed that prunin had lower binding energy and higher binding affinity than glycosides with higher numbers of H-bonds, suggesting that prunin is the best fit to the PTP1B active site cavity. Therefore, in addition to the number of H-bonds present, possible factors affecting the protein binding and PTP1B inhibition of flavanones include their fit to the active site, hydrogen-bonding affinity, Van der Waals interactions, H-bond distance, and H-bond stability. Furthermore, this study clearly depicted the association of the intensity of bioactivity with the arrangement and characterization of the sugar moiety on the flavonoid skeleton.

PTP1B inhibitors from Selaginella tamariscina (Beauv.) Spring and their kinetic properties and molecular docking simulation

Diabetes is one of the most popular worldwide diseases, regulated by the defects in insulin secretion, insulin action, or both. The overexpression of protein tyrosine phosphatase 1B (PTP1B) was found to down-regulate the insulin-receptor activation. PTP1B has been known as a strategy for the treatment of diabetes via the regulation of insulin signal transduction pathway. Herein, we investigated the PTP1B inhibitors isolated from natural sources. The chemical investigation of Selaginella tamariscina (Beauv.) Spring revealed seven unsaturated alkynyl phenols 1-7, four new selaginellins T-W 1-4 together with three known compounds 5-7 isolated from the aerial parts. The structures of the isolates were determined by spectroscopic techniques (1D/2D-NMR, MS, and CD). The inhibitory effects of these isolates on the PTP1B enzyme activity were investigated. Among them, compounds 2-7 significantly exhibited the inhibitory effects with the IC50 values ranging from 4.8 to 15.9μM. Compound 1 moderately displayed the inhibitory activity with an IC50 of 57.9μM. Furthermore, active compounds were discovered from their kinetic and molecular docking analysis. The results revealed that compounds 2 and 4-7 were mixed-competitive inhibitors, whereas compound 3 was a non-competitive inhibitor. This data confirm that these compounds exhibited potential inhibitory effect on the PTP1B enzyme activity.

Computational insights into β-site amyloid precursor protein enzyme 1 (BACE1) inhibition by tanshinones and salvianolic acids from Salvia miltiorrhiza via molecular docking simulations

The rhizome of Salvia miltiorrhiza has emerged as a rich source of natural therapeutic agents, and its several compounds are supposed to exhibit favorable effects on Alzheimers disease (AD). The present work investigate the anti-AD potentials of 12 tanshinones, three salvianolic acids and three caffeic acid derivatives from S. miltiorrhiza via the inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Among the tested compounds, deoxyneocryptotanshinone (1), salvianolic acid A (13) and salvianolic acid C (15) displayed good inhibitory effect on BACE1 with IC50 values of 11.53 ± 1.13, 13.01 ± 0.32 and 9.18 ± 0.03 μM, respectively. Besides this, enzyme kinetic analysis on BACE1 revealed 13, a competitive type inhibitor while 1 and 15 showed mixed-type inhibition. Furthermore, molecular docking simulation displayed negative binding energies (AutoDock 4.2.6 = -10.0 to -7.1 kcal/mol) of 1, 13, and 15 for BACE1, indicating these compounds bound tightly to the active site of the enzyme with low energy and high affinity. The results of the present study clearly demonstrate that S. miltiorrhiza and its constituents have potential anti-AD activity and can be used as a therapeutic agent for the treatment of AD.

PTP1B inhibitory and cytotoxic activities of triterpenoids from the aerial parts of Agrimonia pilosa

Recently, PTP1B inhibitors have become the frontier as possible targeting for anti-cancer and anti-diabetic drugs. Twelve triterpenoids from the aerial parts of Agrimonia pilosa were investigated for PTP1B inhibitory and cytotoxic activities. In the results, compounds 3 (IC50 = 0.50 μM) and 7 (IC50 = 5.88 μM) were found to possess very powerful inhibitory activity against the PTP1B enzyme, comparable to the positive control ursolic acid (IC50 = 6.60 μM). In addition, compounds 1, 2, 4, and 10‒12 showed potent inhibitory effects against PTP1B, with an IC50 range of 13.48‒14.98 μM. In the kinetic assay of the PTP1B enzyme, compounds 1 and 2 were noncompetitive, whereas 7 and 11 showed a mixed type. In the docking analysis, the results showed that different residues of PTP1B interacted with twelve triterpenoids. Furthermore, compounds 6 (IC50 = 3.65 μM) and 12 (IC50 = 1.21 μM) displayed strong cytotoxic effects against the HeLa cell line. Compounds 2 (IC50 = 16.06 μM) and 4 (IC50 = 14.73 μM) showed moderate cytotoxic activities against the HeLa cell line. Compound 2 exhibited comprehensive cytotoxicity against the HL-60 (IC50 = 45.53 μM) and MCF-7 (IC50 = 34.21 μM) cell lines. These results support the use of triterpenoids in traditional medicine for prevention and treatment of diabetes and cancer.Recently, PTP1B inhibitors have become the frontier as possible targeting for anti-cancer and anti-diabetic drugs. Twelve triterpenoids from the aerial parts of Agrimonia pilosa were investigated for PTP1B inhibitory and cytotoxic activities. In the results, compounds 3 (IC50 = 0.50 μM) and 7 (IC50 = 5.88 μM) were found to possess very powerful inhibitory activity against the PTP1B enzyme, comparable to the positive control ursolic acid (IC50 = 6.60 μM). In addition, compounds 1, 2, 4, and 10‒12 showed potent inhibitory effects against PTP1B, with an IC50 range of 13.48‒14.98 μM. In the kinetic assay of the PTP1B enzyme, compounds 1 and 2 were noncompetitive, whereas 7 and 11 showed a mixed type. In the docking analysis, the results showed that different residues of PTP1B interacted with twelve triterpenoids. Furthermore, compounds 6 (IC50 = 3.65 μM) and 12 (IC50 = 1.21 μM) displayed strong cytotoxic effects against the HeLa cell line. Compounds 2 (IC50 = 16.06 μM) and 4 (IC50 = 14.73 μM) showed moderate cytotoxic activities against the HeLa cell line. Compound 2 exhibited comprehensive cytotoxicity against the HL-60 (IC50 = 45.53 μM) and MCF-7 (IC50 = 34.21 μM) cell lines. These results support the use of triterpenoids in traditional medicine for prevention and treatment of diabetes and cancer.

Chalcone derivatives from the root bark of Morus alba L. act as inhibitors of PTP1B and α-glucosidase

As part of our continuing research to obtain pharmacologically active compounds from Morus alba L. (Moraceae), four Diels-Alder type adducts (DAs) [morusalbins A-D], one isoprenylated flavonoid [albanin T], together with twenty-one known phenolic compounds were isolated from its root bark. The chemical structures were established using NMR, MS, and ECD spectra. The DAs including morusalbins A-D, albasin B, macrourin G, yunanensin A, mulberrofuran G and K, and albanol B exhibited strong inhibitory activities against both protein tyrosine phosphatase 1B (PTP1B) (IC50, 1.90-9.67 μM) and α-glucosidase (IC50, 2.29-5.91 μM). In the kinetic study, morusalbin D, albasin B, and macrourin G showed noncompetitive PTP1B inhibition, with Ki values of 0.33, 1.00, and 1.09 μM, respectively. In contrast, these DAs together with yunanensin A produced competitive inhibition of α-glucosidase, with Ki values of 0.64, 0.42, 2.42, and 1.19 μM, respectively. Furthermore, molecular docking studies revealed that these active DAs have high affinity and tight binding capacity towards the active site of PTP1B and α-glucosidase.

Moracin derivatives from Morus Radix as dual BACE1 and cholinesterase inhibitors with antioxidant and anti-glycation capacities

Aims: Morus, a member of the family Moraceae and commonly known as the mulberry, comprises a pharmaceutically important plant group whose major constituents are the moracins. Moracin derivatives have received great attention because they exhibit a diverse range of biological functionalities. However, no studies have considered the anti‐Alzheimers disease (AD) and anti‐glycation potential of moracin derivatives. Main methods: We designed the current study to explore the anti‐AD activity of moracin derivatives via in vitro inhibition of BACE1 and cholinesterase, their antioxidant activity via scavenging ONOO− and ABTS·+ radicals, and their anti‐diabetic activity through inhibition of advanced glycation end‐products (AGEs) formation. Moreover, to define the mechanism of action of moracin derivatives in depth, we performed in silico molecular modeling using a computer‐assisted drug design and modeling program. Key findings: Among the four Morus‐derived moracins tested, moracin S, which has a prenyl moiety in the 2‐aryl benzofuran scaffold, possessed the highest BACE1 inhibitory activity. It also, in a dose‐dependent fashion, decreased ONOO−‐mediated bovine serum albumin (BSA) nitration and formation of AGEs and amyloid cross‐&bgr; structures in the glycated BSA system, and it showed notable radical scavenging activity. In addition, enzyme kinetic and molecular docking studies demonstrated that moracin S is a potent, competitive BACE1 inhibitor that could interact with key catalytic aspartyl residues. Significance: The prenyl moiety in the 2‐aryl benzofuran structure plays a crucial role in inhibition of BACE1. These in vitro and in silico results provide valuable information for the design of anti‐AD drugs. Graphical abstract Figure. No caption available.