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12 pages, 4150 KiB

Open AccessArticle

Discovery of a Novel Inhibitor Structure of Mycobacterium tuberculosis Isocitrate Lyase

by Changyuan Duan, Qihua Jiang, Xue Jiang, Hongwei Zeng, Qiaomin Wu, Yang Yu and Xiaolan Yang

Molecules 2022, 27(8), 2447; https://doi.org/10.3390/molecules27082447 - 11 Apr 2022

Cited by 11 | Viewed by 3068

Abstract

Tuberculosis remains a global threat to public health, and dormant Mycobacterium tuberculosis leads to long-term medication that is harmful to the human body. M. tuberculosis isocitrate lyase (MtICL), which is absent in host cells, is a key rate-limiting enzyme of the [...] Read more.

Tuberculosis remains a global threat to public health, and dormant Mycobacterium tuberculosis leads to long-term medication that is harmful to the human body. M. tuberculosis isocitrate lyase (MtICL), which is absent in host cells, is a key rate-limiting enzyme of the glyoxylic acid cycle and is essential for the survival of dormant M. tuberculosis. The aim of this study was to evaluate natural compounds as potential MtICL inhibitors through docking and experimental verification. Screening of the TCMSP database library was done using Discovery Studio 2019 for molecular docking and interaction analysis, with the putative inhibitors of MtICL, 3-BP, and IA as reference ligands. Daphnetin (MOL005118), with a docking score of 94.8 and -CDOCKER interaction energy of 56 kcal/mol, was selected and verified on MtICL in vitro and M. smegmatis; daphnetin gave an IC₅₀ of 4.34 μg/mL for the MtICL enzyme and an MIC value of 128 μg/mL against M. smegmatis, showing enhanced potential in comparison with 3-BP and IA. The interactions and essential amino acid residues of the protein were analyzed. In summary, natural daphnetin may be a promising new skeleton for the design of inhibitors of MtICL to combat dormant M. tuberculosis. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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16 pages, 4151 KiB

Open AccessArticle

Phytochemical Composition, Antioxidant Activity, α-Glucosidase and Acetylcholinesterase Inhibitory Activity of Quinoa Extract and Its Fractions

by Xi Chen, Xuemei He, Jian Sun and Zhenxing Wang

Molecules 2022, 27(8), 2420; https://doi.org/10.3390/molecules27082420 - 8 Apr 2022

Cited by 14 | Viewed by 2454

Abstract

This study is aimed to evaluate the chemical compositions and biological activities of quinoa, a novel and excellent food crop. Quinoa extract and its fractions were prepared by ethanol extraction and liquid-liquid extraction, including ethanol crude extract, and petroleum ether, chloroform, ethyl acetate [...] Read more.

This study is aimed to evaluate the chemical compositions and biological activities of quinoa, a novel and excellent food crop. Quinoa extract and its fractions were prepared by ethanol extraction and liquid-liquid extraction, including ethanol crude extract, and petroleum ether, chloroform, ethyl acetate (EAF), and n-butanol and water fractions. The total phenolic and flavonoid contents, antioxidant activities, α-glucosidase and acetylcholinesterase inhibitory abilities of the extract and fractions were further determined. Based on these foundations, the chemical composition of the EAF fraction exhibiting the strongest functional activity was analyzed by ultra-performance liquid chromatography-mass spectrometry. The results showed the EAF fraction had the highest phenolic and flavonoid contents, and the highest antioxidant activities, as well as the strongest α-glucosidase and acetylcholinesterase inhibitory abilities, which is even better than the positive control. The phytochemical composition of the EAF fraction indicated that 661 and 243 metabolites were identified in positive and negative ion modes, which were classified into superclass, class and subclass levels, respectively. Phenolic acids and flavonoids were the major bioactive compounds in the EAF fraction. This study found that quinoa, especially its ethyl acetate fraction, had the potential for the development of natural antioxidants, acetylcholinesterase inhibitors, and hypoglycemic agents. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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12 pages, 2514 KiB

Open AccessArticle

Rapid Screening of Lipase Inhibitors from Ophiopogonis Radix Using High-Performance Thin Layer Chromatography by Two Step Gradient Elution Combined with Bioautographic Method

by Xue Hua, Hui-Jie Hong, Dai-Yan Zhang, Qiao Liu, Fong Leong, Qi Yang, Yuan-Jia Hu and Xiao-Jia Chen

Molecules 2022, 27(4), 1155; https://doi.org/10.3390/molecules27041155 - 9 Feb 2022

Cited by 4 | Viewed by 2442

Abstract

In this study, a high-performance thin layer chromatography (HPTLC) method by two step gradient elution with two mobile phases was developed for the simultaneous analysis of seven constituents in Ophiopogonis Radix. The chromatography was performed on silica gel 60 F₂₅₄ plate with [...] Read more.

In this study, a high-performance thin layer chromatography (HPTLC) method by two step gradient elution with two mobile phases was developed for the simultaneous analysis of seven constituents in Ophiopogonis Radix. The chromatography was performed on silica gel 60 F₂₅₄ plate with dichloromethane-methanol-ethyl acetate-water (70:25:12:3, v/v/v/v) and dichloromethane-methanol (300:1, v/v) as the mobile phase for two step gradient elution. Then, the HPTLC profiles were observed after derivatization with 10% sulfuric acid in ethanol solution. The obtained HPTLC images were further analyzed by chemometric approaches and the samples could be clustered based on regions and/or growth years, which were two important factors affecting the constituents in Ophiopogonis Radix. Furthermore, five compounds including ophiopogonin D, ophiopojaponin C, ophiopogonin D’, ophiopogonin C’ and methylophiopogonanone B were screened as potential lipase inhibitors from Ophiopogonis Radix by the HPTLC-bioautographic method. The binding modes and interactions between the five compounds and lipase were further explored by molecular docking analysis. The developed HPTLC method could be used for quality control of Ophiopogonis Radix and screening of the potential lipase inhibitors. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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12 pages, 3396 KiB

Open AccessArticle

Screening of Potential Thrombin and Factor Xa Inhibitors from the Danshen–Chuanxiong Herbal Pair through a Spectrum–Effect Relationship Analysis

by Xu Wang, Dai-Yan Zhang, Shi-Jun Yin, Hui Jiang, Min Lu, Feng-Qing Yang and Yuan-Jia Hu

Molecules 2021, 26(23), 7293; https://doi.org/10.3390/molecules26237293 - 1 Dec 2021

Cited by 12 | Viewed by 2237

Abstract

In this study; a spectrum–effect relationship analysis combined with a high-performance liquid chromatography–mass spectrometry (LC–MS) analysis was established to screen and identify active components that can inhibit thrombin and factor Xa (THR and FXa) in Salviae Miltiorrhizae Radix et Rhizoma–Chuanxiong Rhizoma (Danshen–Chuanxiong) herbal [...] Read more.

In this study; a spectrum–effect relationship analysis combined with a high-performance liquid chromatography–mass spectrometry (LC–MS) analysis was established to screen and identify active components that can inhibit thrombin and factor Xa (THR and FXa) in Salviae Miltiorrhizae Radix et Rhizoma–Chuanxiong Rhizoma (Danshen–Chuanxiong) herbal pair. Ten potential active compounds were predicted through a canonical correlation analysis (CCA), and eight of them were tentatively identified through an LC–MS analysis. Furthermore; the enzyme inhibitory activity of six available compounds; chlorogenic acid; Z-ligustilide; caffeic acid; ferulic acid; tanshinone I and tanshinone IIA; were tested to verify the feasibility of the method. Among them; chlorogenic acid was validated to possess a good THR inhibitory activity with IC₅₀ of 185.08 µM. Tanshinone I and tanshinone IIA are potential FXa inhibitors with IC₅₀ of 112.59 µM and 138.19 µM; respectively. Meanwhile; molecular docking results show that tanshinone I and tanshinone IIA; which both have binding energies of less than −7.0 kcal·mol⁻¹; can interact with FXa by forming H-bonds with residues of SER214; GLY219 and GLN192. In short; the THR and FXa inhibitors in the Danshen–Chuanxiong herbal pair have been successfully characterized through a spectrum–effect relationship analysis and an LC–MS analysis. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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10 pages, 26435 KiB

Open AccessArticle

Theoretical Exploring of a Molecular Mechanism for Melanin Inhibitory Activity of Calycosin in Zebrafish

by Nilupaier Tayier, Ning-Yi Qin, Li-Nan Zhao, Yi Zeng, Yu Wang, Guang Hu and Yuan-Qiang Wang

Molecules 2021, 26(22), 6998; https://doi.org/10.3390/molecules26226998 - 19 Nov 2021

Cited by 9 | Viewed by 2552

Abstract

Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin can lead to a variety of skin disorders. Calycosin is an isoflavone from Astragali Radix, which is a traditional Chinese medicine [...] Read more.

Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin in the human body. Overproduction of melanin can lead to a variety of skin disorders. Calycosin is an isoflavone from Astragali Radix, which is a traditional Chinese medicine that exhibits several pharmacological activities including skin whitening. In our study, the inhibitory effect of calycosin on melanin production is confirmed in a zebrafish in vivo model by comparing with hydroquinone, kojic acid, and arbutin, known as tyrosinase inhibitors. Moreover, the inhibitory kinetics of calycosin on tyrosinase and their binding mechanisms are determined using molecular docking techniques, molecular dynamic simulations, and free energy analysis. The results indicate that calycosin has an obvious inhibitory effect on zebrafish pigmentation at the concentration of 7.5 μM, 15 μM, and 30 μM. The IC₅₀ of calycosin is 30.35 μM, which is lower than hydroquinone (37.35 μM), kojic acid (6.51 × 10³ μM), and arbutin (3.67 × 10⁴ μM). Furthermore, all the results of molecular docking, molecular dynamics simulations, and free energy analysis suggest that calycosin can directly bind to the active site of tyrosinase with very good binding affinity. The study indicates that the combination of computer molecular modeling and zebrafish in vivo assay would be feasible in confirming the result of the in vitro test and illustrating the target-binding information. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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15 pages, 3028 KiB

Open AccessArticle

Screening of Potential Anti-Thrombotic Ingredients from Salvia miltiorrhiza in Zebrafish and by Molecular Docking

by Huilan Tang, Ningyi Qin, Chang Rao, Jiahui Zhu, Haiqiang Wang and Guang Hu

Molecules 2021, 26(22), 6807; https://doi.org/10.3390/molecules26226807 - 11 Nov 2021

Cited by 14 | Viewed by 2332

Abstract

Background: Danshen (DS), the dry root of Salvia miltiorrhiza Bge., has been used in traditional Chinese medicine (TCM) for many years to promote blood circulation and to inhibit thrombosis. However, the active ingredients responsible for the anti-thrombotic effect and the underlying mechanisms are [...] Read more.

Background: Danshen (DS), the dry root of Salvia miltiorrhiza Bge., has been used in traditional Chinese medicine (TCM) for many years to promote blood circulation and to inhibit thrombosis. However, the active ingredients responsible for the anti-thrombotic effect and the underlying mechanisms are yet to be fully elucidated. Methods: Molecular docking was used to predict the active ingredients in DS and their potential targets by calculating the scores of docking between DS ingredients and thrombosis-related proteins. Then, a chemical-induced zebrafish thrombosis model was applied to confirm their anti-thrombotic effects. Result: The molecular docking results indicated that compared to the control ligand, higher docking scores were observed for several compounds in DS, among which salvianolic acid B (SAB), lithospermic acid (LA), rosmarinic acid (MA), and luteolin-7-O-β-d-glucoside (LG) could attenuate zebrafish caudal vein thrombosis and recover the decrease in heart red blood cells (RBCs) in a dose-dependent manner. Conclusions: Our study showed that it is possible to screen the potential active components in natural products by combining the molecular docking method and zebrafish in vivo model. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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17 pages, 2380 KiB

Open AccessArticle

Bio-Mechanism of Catechin as Pheromone Signal Inhibitor: Prediction of Antibacterial Agent Action Mode by In Vitro and In Silico Study

by Dikdik Kurnia, Zenika Febian Ramadhanty, Aprilina Mora Ardani, Achmad Zainuddin, Hendra Dian Adhita Dharsono and Mieke Hemiawati Satari

Molecules 2021, 26(21), 6381; https://doi.org/10.3390/molecules26216381 - 22 Oct 2021

Cited by 9 | Viewed by 2585

Abstract

The utilization of medicinal plants has long been explored for the discovery of antibacterial agents and the most effective mechanisms or new targets that can prevent and control the spread of antibiotic resistance. One kind of bacterial cell wall inhibition is the inactivation [...] Read more.

The utilization of medicinal plants has long been explored for the discovery of antibacterial agents and the most effective mechanisms or new targets that can prevent and control the spread of antibiotic resistance. One kind of bacterial cell wall inhibition is the inactivation of the MurA enzyme that contributes to the formation of peptidoglycan. Another approach is to interfere with the cell–cell communication of bacteria called the Quorum sensing (QS) system. The blocking of auto-inducer such as gelatinase biosynthesis-activating pheromone (GBAP) can also suppress the virulence factors of gelatinase and serine protease. This research, in particular, aims to analyze lead compounds as antibacterial and anti-QS agents from Gambir (Uncaria gambir Roxburgh) through protein inhibition by in silico study. Antibacterial agents were isolated by bioactivity-guided isolation using a combination of chromatographic methods, and their chemical structures were determined by spectroscopic analysis methods. The in vitro antibacterial activity was evaluated by disc diffusion methods to determine inhibitory values. Meanwhile, in the in silico analysis, the compound of Uncaria gambir was used as ligand and compared with fosfomycin, ambuic acid, quercetin, and taxifolin as the standard ligand. These ligands were attached to MurA, GBAP, gelatinase, and serine proteases using Autodock Vina in PyRx 0.8 followed by PYMOL for combining the ligand conformation and proteins. plus programs to explore the complex, and visualized by Discovery Studio 2020 Client program. The antibacterial agent was identified as catechin that showed inhibitory activity against Enterococcus faecalis ATCC 29212 with inhibition zones of 11.70 mm at 10%, together with MIC and MBC values of 0.63 and 1.25 μg/mL, respectively. In the in silico study, the molecular interaction of catechin with MurA, GBAP, and gelatinase proteins showed good binding energy compared with two positive controls, namely fosfomycin and ambuic acid. It is better to use catechin–MurA (−8.5 Kcal/mol) and catechin–gelatinase (−7.8 Kcal/mol), as they have binding energies which are not marginally different from quercetin and taxifolin. On the other hand, the binding energy of serine protease is lower than quercetin, taxifolin, and ambuic acid. Based on the data, catechin has potency as an antibacterial through the inhibition of GBAP proteins, gelatinase, and serine protease that play a role in the QS system. This is the first discovery of the potential of catechin as an alternative antibacterial agent with an effective mechanism to prevent and control oral disease affected by antibiotic resistance. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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19 pages, 7212 KiB

Open AccessArticle

Validation of the Antioxidant and Enzyme Inhibitory Potential of Selected Triterpenes Using In Vitro and In Silico Studies, and the Evaluation of Their ADMET Properties

by Nilufar Z. Mamadalieva, Fadia S. Youssef, Hidayat Hussain, Gokhan Zengin, Adriano Mollica, Nawal M. Al Musayeib, Mohamed L. Ashour, Bernhard Westermann and Ludger A. Wessjohann

Molecules 2021, 26(21), 6331; https://doi.org/10.3390/molecules26216331 - 20 Oct 2021

Cited by 32 | Viewed by 2902

Abstract

The antioxidant and enzyme inhibitory potential of fifteen cycloartane-type triterpenes’ potentials were investigated using different assays. In the phosphomolybdenum method, cycloalpioside D (6) (4.05 mmol TEs/g) showed the highest activity. In 1,1-diphenyl-2-picrylhydrazyl (DPPH*) radical and 2,2′-azino-bis(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) cation radical scavenging [...] Read more.

The antioxidant and enzyme inhibitory potential of fifteen cycloartane-type triterpenes’ potentials were investigated using different assays. In the phosphomolybdenum method, cycloalpioside D (6) (4.05 mmol TEs/g) showed the highest activity. In 1,1-diphenyl-2-picrylhydrazyl (DPPH*) radical and 2,2′-azino-bis(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) cation radical scavenging assays, cycloorbicoside A-7-monoacetate (2) (5.03 mg TE/g) and cycloorbicoside B (10) (10.60 mg TE/g) displayed the highest activities, respectively. Oleanolic acid (14) (51.45 mg TE/g) and 3-O-β-d-xylopyranoside-(23R,24S)-16β,23;16α,24-diepoxycycloart-25(26)-en-3β,7β-diol 7-monoacetate (4) (13.25 mg TE/g) revealed the highest reducing power in cupric ion-reducing activity (CUPRAC) and ferric-reducing antioxidant power (FRAP) assays, respectively. In metal-chelating activity on ferrous ions, compound 2 displayed the highest activity estimated by 41.00 mg EDTAE/g (EDTA equivalents/g). The tested triterpenes showed promising AChE and BChE inhibitory potential with 3-O-β-d-xylopyranoside-(23R,24S)-16β,23;16α,24-diepoxycycloart-25(26)-en-3β,7β-diol 2′,3′,4′,7-tetraacetate (3), exhibiting the highest inhibitory activity as estimated from 5.64 and 5.19 mg GALAE/g (galantamine equivalent/g), respectively. Compound 2 displayed the most potent tyrosinase inhibitory activity (113.24 mg KAE/g (mg kojic acid equivalent/g)). Regarding α-amylase and α-glucosidase inhibition, 3-O-β-d-xylopyranoside-(23R,24S)-16β,23;16α,24-diepoxycycloart-25(26)-en-3β,7β-diol (5) (0.55 mmol ACAE/g) and compound 3 (25.18 mmol ACAE/g) exerted the highest activities, respectively. In silico studies focused on compounds 2, 6, and 7 as inhibitors of tyrosinase revealed that compound 2 displayed a good ranking score (−7.069 kcal/mole) and also that the ΔG free-binding energy was the highest among the three selected compounds. From the ADMET/TOPKAT prediction, it can be concluded that compounds 4 and 5 displayed the best pharmacokinetic and pharmacodynamic behavior, with considerable activity in most of the examined assays. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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12 pages, 2316 KiB

Open AccessArticle

Rapid Screening Alpha-Glucosidase Inhibitors from Polygoni Vivipari Rhizoma by Multi-Step Matrix Solid-Phase Dispersion, Ultrafiltration and HPLC

by Haoxiang Li, Zhuobin He, Qianhui Shen, Weifeng Fan, Guoying Tan, Yuansheng Zou, Quanxi Mei and Zhengming Qian

Molecules 2021, 26(20), 6111; https://doi.org/10.3390/molecules26206111 - 10 Oct 2021

Cited by 10 | Viewed by 1959

Abstract

Polygoni Vivipari Rhizoma (PVR), the dried root of Polygonum viviparum, has been used as herbal medicine in China for a long time. In the present study, a new method based on multi-step matrix solid-phase dispersion (MSPD), ultrafiltration and high performance liquid chromatography [...] Read more.

Polygoni Vivipari Rhizoma (PVR), the dried root of Polygonum viviparum, has been used as herbal medicine in China for a long time. In the present study, a new method based on multi-step matrix solid-phase dispersion (MSPD), ultrafiltration and high performance liquid chromatography (HPLC) for screening alpha-glucosidase inhibitors (AGIs) from PVR was proposed. First, three different PVR extractions were prepared by multi-step MSPD with 15% methanol, 60% methanol and 100% methanol. Second, the alpha-glucosidase inhibition tests for the three extracts were carried out, and the 60% methanol extraction showed the best activity. Then, the AGIs screening experiment was performed with ultrafiltration and HPLC analysis using the 60% methanol extraction. Seven binding components (quercetin−3−O−vicianoside, quercetin 3−O−neohesperidoside, rutin, hyperoside, quercetin 3−O−glucuronide, luteolin−7−O−neohesperidoside, kaempferol 3−glucuronide) were found. These seven components were further validated as the AGIs by molecular docking analysis. The developed method was a rapid and efficient tool for screening AGIs from PVR, which provided scientific data for the bioactive components study of PVR. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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13 pages, 1465 KiB

Open AccessArticle

Toxicity of Bioactive Molecule Andrographolide against Spodoptera litura Fab and Its Binding Potential with Detoxifying Enzyme Cytochrome P450

by Edward-Sam Edwin, Prabhakaran Vasantha-Srinivasan, Sengottayan Senthil-Nathan, Muthiah Chellappandian, Sengodan Karthi, Radhakrishnan Narayanaswamy, Vethamonickam Stanley-Raja, Haridoss Sivanesh, Ramakrishnan Ramasubramanian, Asma A. Al-Huqail, Faheema Khan, Patcharin Krutmuang, Ahmed Abdel-Megeed, Aml Ghaith and Chae-Hoon Paik

Molecules 2021, 26(19), 5982; https://doi.org/10.3390/molecules26195982 - 2 Oct 2021

Cited by 15 | Viewed by 3754

Abstract

Spodoptera litura Fab. is a polyphagous pest causing damage to many agriculture crops leading to yield loss. Recurrent usage of synthetic pesticides to control this pest has resulted in resistance development. Plant-derived diterpenoid compound andrographolide was isolated from the leaves of Andrographis paniculata. [...] Read more.

Spodoptera litura Fab. is a polyphagous pest causing damage to many agriculture crops leading to yield loss. Recurrent usage of synthetic pesticides to control this pest has resulted in resistance development. Plant-derived diterpenoid compound andrographolide was isolated from the leaves of Andrographis paniculata. It was analysed by gas chromatography-mass spectroscopy and quantified by HPLC. Nutritional indices and digestive enzymatic profile were evaluated. Third, fourth and fifth instar larvae were treated with different concentrations of andrographolide. At 3, 6 and 9 ppm-treated concentrations the larvae showed decreased RGR, RCR, ECI, ECD values with adverse increase in AD. The digestive enzymes were significantly inhibited when compared with control. Conspicuously, andrographolide showed pronounced mortality of S. litura by inhibition of enzyme secretion and intake of food. The binding ability of andrographolide with CYTP450 showed high affinity with low binding energy. Andrographolide has the potential to be exploited as a biocontrol agent against S. litura as an eco-friendly pesticide. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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11 pages, 2902 KiB

Open AccessArticle

Personal Glucose Meter for α-Glucosidase Inhibitor Screening Based on the Hydrolysis of Maltose

by Tao Tian, Guo-Ying Chen, Hao Zhang and Feng-Qing Yang

Molecules 2021, 26(15), 4638; https://doi.org/10.3390/molecules26154638 - 30 Jul 2021

Cited by 14 | Viewed by 3452

Abstract

As a key enzyme regulating postprandial blood glucose, α-Glucosidase is considered to be an effective target for the treatment of diabetes mellitus. In this study, a simple, rapid, and effective method for enzyme inhibitors screening assay was established based on α-glucosidase catalyzes reactions [...] Read more.

As a key enzyme regulating postprandial blood glucose, α-Glucosidase is considered to be an effective target for the treatment of diabetes mellitus. In this study, a simple, rapid, and effective method for enzyme inhibitors screening assay was established based on α-glucosidase catalyzes reactions in a personal glucose meter (PGM). α-glucosidase catalyzes the hydrolysis of maltose to produce glucose, which triggers the reduction of ferricyanide (K₃[Fe(CN)₆]) to ferrocyanide (K₄[Fe(CN)₆]) and generates the PGM detectable signals. When the α-glucosidase inhibitor (such as acarbose) is added, the yield of glucose and the readout of PGM decreased accordingly. This method can achieve the direct determination of α-glucosidase activity by the PGM as simple as the blood glucose tests. Under the optimal experimental conditions, the developed method was applied to evaluate the inhibitory activity of thirty-four small-molecule compounds and eighteen medicinal plants extracts on α-glucosidase. The results exhibit that lithospermic acid (52.5 ± 3.0%) and protocatechualdehyde (36.8 ± 2.8%) have higher inhibitory activity than that of positive control acarbose (31.5 ± 2.5%) at the same final concentration of 5.0 mM. Besides, the lemon extract has a good inhibitory effect on α-glucosidase with a percentage of inhibition of 43.3 ± 3.5%. Finally, the binding sites and modes of four active small-molecule compounds to α-glucosidase were investigated by molecular docking analysis. These results indicate that the PGM method is feasible to screening inhibitors from natural products with simple and rapid operations. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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18 pages, 4184 KiB

Open AccessArticle

Phytochemical Composition, Antioxidant Activity, and Enzyme Inhibitory Activities (α-Glucosidase, Xanthine Oxidase, and Acetylcholinesterase) of Musella lasiocarpa

by Rurui Li, Yuerong Ru, Zhenxing Wang, Xiahong He, Kin-Weng Kong, Tingting Zheng and Xuechun Zhang

Molecules 2021, 26(15), 4472; https://doi.org/10.3390/molecules26154472 - 24 Jul 2021

Cited by 11 | Viewed by 3191

Abstract

In this study, we aimed to investigate the chemical components and biological activities of Musella lasiocarpa, a special flower that is edible and has functional properties. The crude methanol extract and its four fractions (petroleum ether, ethyl acetate, n-butanol, and aqueous fractions) [...] Read more.

In this study, we aimed to investigate the chemical components and biological activities of Musella lasiocarpa, a special flower that is edible and has functional properties. The crude methanol extract and its four fractions (petroleum ether, ethyl acetate, n-butanol, and aqueous fractions) were tested for their total antioxidant capacity, followed by their α-glucosidase, acetylcholinesterase, and xanthine oxidase inhibitory activities. Among the samples, the highest total phenolic and total flavonoid contents were found in the ethyl acetate (EtOAc) fraction (224.99 mg GAE/g DE) and crude methanol extract (187.81 mg QE/g DE), respectively. The EtOAc fraction of Musella lasiocarpa exhibited the strongest DPPH· scavenging ability, ABTS·⁺ scavenging ability, and α-glucosidase inhibitory activity with the IC₅₀ values of 22.17, 12.10, and 125.66 μg/mL, respectively. The EtOAc fraction also showed the strongest ferric reducing antioxidant power (1513.89 mg FeSO₄/g DE) and oxygen radical absorbance capacity ability (524.11 mg Trolox/g DE), which were higher than those of the control BHT. In contrast, the aqueous fraction demonstrated the highest acetylcholinesterase inhibitory activity (IC₅₀ = 10.11 μg/mL), and the best xanthine oxidase inhibitory ability (IC₅₀ = 5.23 μg/mL) was observed from the crude methanol extract as compared with allopurinol (24.85 μg/mL). The HPLC-MS/MS and GC-MS analyses further revealed an impressive arsenal of compounds, including phenolic acids, fatty acids, esters, terpenoids, and flavonoids, in the most biologically active EtOAc fraction. Taken together, this is the first report indicating the potential of Musella lasiocarpa as an excellent natural source of antioxidants with possible therapeutic, nutraceutical, and functional food applications. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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21 pages, 2531 KiB

Open AccessArticle

Indole- and Pyrazole-Glycyrrhetinic Acid Derivatives as PTP1B Inhibitors: Synthesis, In Vitro and In Silico Studies

by Ledy De-la-Cruz-Martínez, Constanza Duran-Becerra, Martin González-Andrade, José C. Páez-Franco, Juan Manuel Germán-Acacio, Julio Espinosa-Chávez, J. Martin Torres-Valencia, Jaime Pérez-Villanueva, Juan Francisco Palacios-Espinosa, Olivia Soria-Arteche and Francisco Cortés-Benítez

Molecules 2021, 26(14), 4375; https://doi.org/10.3390/molecules26144375 - 20 Jul 2021

Cited by 17 | Viewed by 4019

Abstract

Regulating insulin and leptin levels using a protein tyrosine phosphatase 1B (PTP1B) inhibitor is an attractive strategy to treat diabetes and obesity. Glycyrrhetinic acid (GA), a triterpenoid, may weakly inhibit this enzyme. Nonetheless, semisynthetic derivatives of GA have not been developed as PTP1B [...] Read more.

Regulating insulin and leptin levels using a protein tyrosine phosphatase 1B (PTP1B) inhibitor is an attractive strategy to treat diabetes and obesity. Glycyrrhetinic acid (GA), a triterpenoid, may weakly inhibit this enzyme. Nonetheless, semisynthetic derivatives of GA have not been developed as PTP1B inhibitors to date. Herein we describe the synthesis and evaluation of two series of indole- and N-phenylpyrazole-GA derivatives (4a–f and 5a–f). We measured their inhibitory activity and enzyme kinetics against PTP1B using p-nitrophenylphosphate (pNPP) assay. GA derivatives bearing substituted indoles or N-phenylpyrazoles fused to their A-ring showed a 50% inhibitory concentration for PTP1B in a range from 2.5 to 10.1 µM. The trifluoromethyl derivative of indole-GA (4f) exhibited non-competitive inhibition of PTP1B as well as higher potency (IC₅₀ = 2.5 µM) than that of positive controls ursolic acid (IC₅₀ = 5.6 µM), claramine (IC₅₀ = 13.7 µM) and suramin (IC₅₀ = 4.1 µM). Finally, docking and molecular dynamics simulations provided the theoretical basis for the favorable activity of the designed compounds. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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13 pages, 3016 KiB

Open AccessArticle

Evaluation of Enzyme Inhibitory Activity of Flavonoids by Polydopamine-Modified Hollow Fiber-Immobilized Xanthine Oxidase

by Cong-Peng Zhao, Guo-Ying Chen, Yuan Wang, Hua Chen, Jia-Wen Yu and Feng-Qing Yang

Molecules 2021, 26(13), 3931; https://doi.org/10.3390/molecules26133931 - 28 Jun 2021

Cited by 8 | Viewed by 2832

Abstract

In this study, a polydopamine (PDA)-modified hollow fiber-immobilized xanthine oxidase (XOD) was prepared for screening potential XOD inhibitors from flavonoids. Several parameters for the preparation of PDA-modified hollow fiber-immobilized XOD, including the dopamine concentration, modification time, XOD concentration and immobilization time, were optimized. [...] Read more.

In this study, a polydopamine (PDA)-modified hollow fiber-immobilized xanthine oxidase (XOD) was prepared for screening potential XOD inhibitors from flavonoids. Several parameters for the preparation of PDA-modified hollow fiber-immobilized XOD, including the dopamine concentration, modification time, XOD concentration and immobilization time, were optimized. The results show that the optimal conditions for immobilized XOD activity were a dopamine concentration of 2.0 mg/mL in 10.0 mM Tris-HCl buffer (pH 8.5), a modification time of 3.0 h, an XOD concentration of 1000 μg/mL in 10.0 mM phosphate buffer (pH 7.5) and an immobilization time of 3.0 h. Subsequently, the enzymatic reaction conditions such as the pH value and temperature were investigated, and the enzyme kinetics and inhibition parameters were determined. The results indicate that the optimal pH value (7.5) and temperature (37 °C) of the PDA-modified hollow fiber-immobilized XOD were consistent with the free enzyme. Moreover, the PDA-modified hollow fiber-immobilized XOD could still maintain above 50% of its initial immobilized enzyme activity after seven consecutive cycles. The Michaelis–Menten constant (K_m) and the half-maximal inhibitory concentration (IC₅₀) of allopurinol on the immobilized XOD were determined as 0.25 mM and 23.2 μM, respectively. Furthermore, the PDA-modified hollow fiber-immobilized XOD was successfully applied to evaluate the inhibitory activity of eight flavonoids. Quercetin, apigenin, puerarin and epigallocatechin showed a good inhibition effect, and their percentages of inhibition were (79.86 ± 3.50)%, (80.98 ± 0.64)%, (61.15 ± 6.26)% and (54.92 ± 0.41)%, respectively. Finally, molecular docking analysis further verified that these four active compounds could bind to the amino acid residues in the XOD active site. In summary, the PDA-modified hollow fiber-immobilized XOD is an efficient method for the primary screening of XOD inhibitors from natural products. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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Review

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18 pages, 1987 KiB

Open AccessReview

Enzyme Activity of Natural Products on Cytochrome P450

by Hua-Li Zuo, Hsi-Yuan Huang, Yang-Chi-Dung Lin, Xiao-Xuan Cai, Xiang-Jun Kong, Dai-Lin Luo, Yu-Heng Zhou and Hsien-Da Huang

Molecules 2022, 27(2), 515; https://doi.org/10.3390/molecules27020515 - 14 Jan 2022

Cited by 26 | Viewed by 5703

Abstract

Drug-metabolizing enzymes, particularly the cytochrome P450 (CYP450) monooxygenases, play a pivotal role in pharmacokinetics. CYP450 enzymes can be affected by various xenobiotic substrates, which will eventually be responsible for most metabolism-based herb–herb or herb–drug interactions, usually involving competition with another drug for the [...] Read more.

Drug-metabolizing enzymes, particularly the cytochrome P450 (CYP450) monooxygenases, play a pivotal role in pharmacokinetics. CYP450 enzymes can be affected by various xenobiotic substrates, which will eventually be responsible for most metabolism-based herb–herb or herb–drug interactions, usually involving competition with another drug for the same enzyme binding site. Compounds from herbal or natural products are involved in many scenarios in the context of such interactions. These interactions are decisive both in drug discovery regarding the synergistic effects, and drug application regarding unwanted side effects. Herein, this review was conducted as a comprehensive compilation of the effects of herbal ingredients on CYP450 enzymes. Nearly 500 publications reporting botanicals’ effects on CYP450s were collected and analyzed. The countries focusing on this topic were summarized, the identified herbal ingredients affecting enzyme activity of CYP450s, as well as methods identifying the inhibitory/inducing effects were reviewed. Inhibitory effects of botanicals on CYP450 enzymes may contribute to synergistic effects, such as herbal formulae/prescriptions, or lead to therapeutic failure, or even increase concentrations of conventional medicines causing serious adverse events. Conducting this review may help in metabolism-based drug combination discovery, and in the evaluation of the safety profile of natural products used therapeutically. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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13 pages, 1374 KiB

Open AccessReview

Non-Alkaloid Cholinesterase Inhibitory Compounds from Natural Sources

by Alfred Ngenge Tamfu, Selcuk Kucukaydin, Balakyz Yeskaliyeva, Mehmet Ozturk and Rodica Mihaela Dinica

Molecules 2021, 26(18), 5582; https://doi.org/10.3390/molecules26185582 - 14 Sep 2021

Cited by 31 | Viewed by 4674

Abstract

Alzheimer’s disease (AD) is a severe neurodegenerative disorder of different brain regions accompanied by distresses and affecting more than 25 million people in the world. This progressive brain deterioration affects the central nervous system and has negative impacts on a patient’s daily activities [...] Read more.

Alzheimer’s disease (AD) is a severe neurodegenerative disorder of different brain regions accompanied by distresses and affecting more than 25 million people in the world. This progressive brain deterioration affects the central nervous system and has negative impacts on a patient’s daily activities such as memory impairment. The most important challenge concerning AD is the development of new drugs for long-term treatment or prevention, with lesser side effects and greater efficiency as cholinesterases inhibitors and the ability to remove amyloid-beta(Aβ) deposits and other related AD neuropathologies. Natural sources provide promising alternatives to synthetic cholinesterase inhibitors and many have been reported for alkaloids while neglecting other classes with potential cholinesterase inhibition. This review summarizes information about the therapeutic potential of small natural molecules from medicinal herbs, belonging to terpenoids, coumarins, and phenolic compounds, and others, which have gained special attention due to their specific modes of action and their advantages of low toxicity and high efficiency in the treatment of AD. Some show superior drug-like features in comparison to synthetic cholinesterase inhibitors. We expect that the listed phytoconstituents in this review will serve as promising tools and chemical scaffolds for the discovery of new potent therapeutic leads for the amelioration and treatment of Alzheimer’s disease. Full article

(This article belongs to the Special Issue Discovery of Enzyme Inhibitors from Natural Products)

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