Editorial

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4 pages, 189 KiB

Open AccessEditorial

Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs

by

Paolo Paoli

Biomolecules 2021, 11(2), 133; https://doi.org/10.3390/biom11020133 - 20 Jan 2021

Cited by 3 | Viewed by 1691

Abstract

For thousands of years, human beings have used natural products for the treatment of various types of pathologies [...] Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

Research

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22 pages, 2482 KiB

Open AccessArticle

Identification of Putative Non-Substrate-Based XT-I Inhibitors by Natural Product Library Screening

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Biomolecules 2020, 10(10), 1467; https://doi.org/10.3390/biom10101467 - 21 Oct 2020

Cited by 8 | Viewed by 2244

Abstract

Fibroproliferative diseases are characterized by excessive accumulation of extracellular matrix (ECM) components leading to organ dysfunction. This process is characterized by an increase in myofibroblast content and enzyme activity of xylosyltransferase-I (XT-I), the initial enzyme in proteoglycan (PG) biosynthesis. Therefore, the inhibition of [...] Read more.

Fibroproliferative diseases are characterized by excessive accumulation of extracellular matrix (ECM) components leading to organ dysfunction. This process is characterized by an increase in myofibroblast content and enzyme activity of xylosyltransferase-I (XT-I), the initial enzyme in proteoglycan (PG) biosynthesis. Therefore, the inhibition of XT-I could be a promising treatment for fibrosis. We used a natural product-inspired compound library to identify non-substrate-based inhibitors of human XT-I by UPLC-MS/MS. We combined this cell-free approach with virtual and molecular biological analyses to confirm and prioritize the inhibitory potential of the compounds identified. The characterization for compound potency in TGF-β1-driven XYLT1 transcription regulation in primary dermal human fibroblasts (key cells in ECM remodeling) was addressed by gene expression analysis. Consequently, we identified amphotericin B and celastrol as new non-substrate-based XT-I protein inhibitors. Their XT-I inhibitory effects were mediated by an uncompetitive or a competitive inhibition mode, respectively. Both compounds reduced the cellular XYLT1 expression level and XT-I activity. We showed that these cellular inhibitor-mediated changes involve the TGF-β and microRNA-21 signaling pathway. The results of our study provide a strong rationale for the further optimization and future usage of the XT-I inhibitors identified as promising therapeutic agents of fibroproliferative diseases. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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14 pages, 18129 KiB

Open AccessFeature PaperArticle

The Cytokine IL-1β and Piperine Complex Surveyed by Experimental and Computational Molecular Biophysics

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Gabriel Zazeri

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Ana Paula Ribeiro Povinelli

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Marcelo de Freitas Lima

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Marinônio Lopes Cornélio

Biomolecules 2020, 10(9), 1337; https://doi.org/10.3390/biom10091337 - 18 Sep 2020

Cited by 6 | Viewed by 2150

Abstract

The bioactive piperine, a compound found in some pepper species, has been widely studied because of its therapeutic properties that include the inhibition of an important inflammation pathway triggered by interleukin-1 beta (IL-1β). However, investigation into the molecular interactions between IL-1β and piperine [...] Read more.

The bioactive piperine, a compound found in some pepper species, has been widely studied because of its therapeutic properties that include the inhibition of an important inflammation pathway triggered by interleukin-1 beta (IL-1β). However, investigation into the molecular interactions between IL-1β and piperine is not reported in the literature. Here, we present for the first time the characterisation of the complex formed by IL-1β and piperine through experimental and computational molecular biophysical analyses. Fluorescence spectroscopy unveiled the presence of one binding site for piperine with an affinity constant of 14.3 × 10⁴ M⁻¹ at 298 K. The thermodynamic analysis indicated that the interaction with IL-1β was spontaneous (∆G = −25 kJ/mol) and, when split into enthalpic and entropic contributions, the latter was more significant. Circular dichroism spectroscopy showed that piperine did not affect IL-1β secondary structure (~2%) and therefore its stability. The set of experimental data parameterized the computational biophysical approach. Through molecular docking, the binding site micro-environment was revealed to be composed mostly by non-polar amino acids. Furthermore, molecular dynamics, along with umbrella sampling, are in agreement with the thermodynamic parameters obtained by fluorescence assays and showed that large protein movements are not present in IL-1β, corroborating the circular dichroism data. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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17 pages, 12871 KiB

Open AccessArticle

Isolation of Cysteine-Rich Peptides from Citrullus colocynthis

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Behzad Shahin-Kaleybar

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Ali Niazi

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Alireza Afsharifar

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Ghorbanali Nematzadeh

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Biomolecules 2020, 10(9), 1326; https://doi.org/10.3390/biom10091326 - 16 Sep 2020

Cited by 5 | Viewed by 3632

Abstract

The plant Citrullus colocynthis, a member of the squash (Cucurbitaceae) family, has a long history in traditional medicine. Based on the ancient knowledge about the healing properties of herbal preparations, plant-derived small molecules, e.g., salicylic acid, or quinine, have been integral to [...] Read more.

The plant Citrullus colocynthis, a member of the squash (Cucurbitaceae) family, has a long history in traditional medicine. Based on the ancient knowledge about the healing properties of herbal preparations, plant-derived small molecules, e.g., salicylic acid, or quinine, have been integral to modern drug discovery. Additionally, many plant families, such as Cucurbitaceae, are known as a rich source for cysteine-rich peptides, which are gaining importance as valuable pharmaceuticals. In this study, we characterized the C. colocynthis peptidome using chemical modification of cysteine residues, and mass shift analysis via matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. We identified the presence of at least 23 cysteine-rich peptides in this plant, and eight novel peptides, named citcol-1 to -8, with a molecular weight between ~3650 and 4160 Da, were purified using reversed-phase high performance liquid chromatography (HPLC), and their amino acid sequences were determined by de novo assignment of b- and y-ion series of proteolytic peptide fragments. In silico analysis of citcol peptides revealed a high sequence similarity to trypsin inhibitor peptides from Cucumis sativus, Momordica cochinchinensis, Momordica macrophylla and Momordica sphaeroidea. Using genome/transcriptome mining it was possible to identify precursor sequences of this peptide family in related Cucurbitaceae species that cluster into trypsin inhibitor and antimicrobial peptides. Based on our analysis, the presence or absence of a crucial Arg/Lys residue at the putative P1 position may be used to classify these common cysteine-rich peptides by functional properties. Despite sequence homology and the common classification into the inhibitor cysteine knot family, these peptides appear to have diverse and additional bioactivities yet to be revealed. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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20 pages, 8913 KiB

Open AccessArticle

Identification and Target-Modification of SL-BBI: A Novel Bowman–Birk Type Trypsin Inhibitor from Sylvirana latouchii

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Biomolecules 2020, 10(9), 1254; https://doi.org/10.3390/biom10091254 - 28 Aug 2020

Cited by 7 | Viewed by 2348

Abstract

The peptides from the ranacyclin family share similar active disulphide loop with plant-derived Bowman–Birk type inhibitors, some of which have the dual activities of trypsin inhibition and antimicrobial. Herein, a novel Bowman–Birk type trypsin inhibitor of the ranacyclin family was identified from the [...] Read more.

The peptides from the ranacyclin family share similar active disulphide loop with plant-derived Bowman–Birk type inhibitors, some of which have the dual activities of trypsin inhibition and antimicrobial. Herein, a novel Bowman–Birk type trypsin inhibitor of the ranacyclin family was identified from the skin secretion of broad-folded frog (Sylvirana latouchii) by molecular cloning method and named as SL-BBI. After chemical synthesis, it was proved to be a potent inhibitor of trypsin with a Ki value of 230.5 nM and showed weak antimicrobial activity against tested microorganisms. Modified analogue K-SL maintains the original inhibitory activity with a Ki value of 77.27 nM while enhancing the antimicrobial activity. After the substitution of active P1 site to phenylalanine and P2′ site to isoleucine, F-SL regenerated its inhibitory activity on chymotrypsin with a Ki value of 309.3 nM and exhibited antiproliferative effects on PC-3, MCF-7 and a series of non-small cell lung cancer cell lines without cell membrane damage. The affinity of F-SL for the β subunits in the yeast 20S proteasome showed by molecular docking simulations enriched the understanding of the possible action mode of Bowman–Birk type inhibitors. Further mechanistic studies have shown that F-SL can activate caspase 3/7 in H157 cells and induce apoptosis, which means it has the potential to become an anticancer agent. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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13 pages, 1637 KiB

Open AccessArticle

Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against Candida Yeast by Inhibition of Lanosterol 14-Alpha Demethylase

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Biomolecules 2020, 10(8), 1101; https://doi.org/10.3390/biom10081101 - 24 Jul 2020

Cited by 9 | Viewed by 2760

Abstract

Candida species cause an opportunistic yeast infection called Candidiasis, which is responsible for more than 50,000 deaths every year around the world. Effective treatments against candidiasis caused by non-albicans Candida species such as C. glabrata, C. parapsilosis, C. aureus, and C. krusei are [...] Read more.

Candida species cause an opportunistic yeast infection called Candidiasis, which is responsible for more than 50,000 deaths every year around the world. Effective treatments against candidiasis caused by non-albicans Candida species such as C. glabrata, C. parapsilosis, C. aureus, and C. krusei are limited due to severe resistance to conventional antifungal drugs. Natural drimane sesquiterpenoids have shown promising antifungal properties against Candida yeast and have emerged as valuable candidates for developing new candidiasis therapies. In this work, we isolated isodrimeninol (C1) from barks of Drimys winteri and used it as starting material for the hemi-synthesis of four sesquiterpenoids by oxidation with pyridinium chlorochromate (PCC). The structure of the products (C2, C3, C4, and C5) was elucidated by 1D and 2D NMR spectroscopy resulting in C4 being a novel compound. Antifungal activity assays against C. albicans, C. glabrata, and C. krusei revealed that C4 exhibited an increased activity (IC₅₀ of 75 μg/mL) compared to C1 (IC₅₀ of 125 μg/mL) in all yeast strains. The antifungal activity of C1 and C4 was rationalized in terms of their capability to inhibit lanosterol 14-alpha demethylase using molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations. In silico analysis revealed that C1 and C4 bind to the outermost region of the catalytic site of 14-alpha demethylase and block the entrance of lanosterol (LAN) to the catalytic pocket. Binding free energy estimates suggested that C4 forms a more stable complex with the enzyme than C1, in agreement with the experimental evidence. Based on this new approach it is possible to design new drimane-type sesquiterpenoids for the control of Candida species as inhibitors of 14-alpha demethylase. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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18 pages, 1994 KiB

Open AccessArticle

α-Glucosidase Inhibitory Activity of Tannat Grape Phenolic Extracts in Relation to Their Ripening Stages

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Biomolecules 2020, 10(8), 1088; https://doi.org/10.3390/biom10081088 - 22 Jul 2020

Cited by 13 | Viewed by 2735

Abstract

The present study aimed to screen grape extracts as novel α-glucosidase inhibitors to prevent type-2 diabetes and hyperglycemia. The total polyphenol content (TPC) was measured by Folin-Ciocalteu assay and the stilbene, anthocyanin and flavan-3-ol compounds were measured by Ultra High-Performance Liquid Chromatography coupled [...] Read more.

The present study aimed to screen grape extracts as novel α-glucosidase inhibitors to prevent type-2 diabetes and hyperglycemia. The total polyphenol content (TPC) was measured by Folin-Ciocalteu assay and the stilbene, anthocyanin and flavan-3-ol compounds were measured by Ultra High-Performance Liquid Chromatography coupled to Mass Spectrometry (UHPLC-MS). The α-glucosidase inhibitory of seed and skin Tannat grape extracts at four ripening stages were investigated. The highest TPC values were measured in seeds at the “veraison stage” (65.29 ± 5.33 g of Gallic Acid Equivalent (GAE) per kilogram of Fresh Weight (FW)). This was in accordance with the high flavan-3-ol contents measured for these two extracts (43.22 ± 2.59 and 45.45 ± 6.48 g/kg of seeds FW, respectively). The skin and seed extracts at the first stage of ripening exerted strong α-glucosidase inhibition, exceeding 95% (p < 0.05). A high linear correlation (R = 0.723, p ≤ 0.05) was observed between flavan-3-ol contents and the α-glucosidase inhibitory activity. The stilbene contents and this activity were moderately to strongly anti-correlated (R = –0.828, p ≤ 0.05 for trans-resveratrol). The enzyme kinetic studies revealed a mixed type of inhibition. This study brings promising results for the therapeutic potential of seed and skin Tannat grape extracts as a functional food product with anti-diabetic activity. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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26 pages, 4792 KiB

Open AccessArticle

Aldose Reductase Differential Inhibitors in Green Tea

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Biomolecules 2020, 10(7), 1003; https://doi.org/10.3390/biom10071003 - 06 Jul 2020

Cited by 12 | Viewed by 2616

Abstract

Aldose reductase (AKR1B1), the first enzyme in the polyol pathway, is likely involved in the onset of diabetic complications. Differential inhibition of AKR1B1 has been proposed to counteract the damaging effects linked to the activity of the enzyme while preserving its detoxifying ability. [...] Read more.

Aldose reductase (AKR1B1), the first enzyme in the polyol pathway, is likely involved in the onset of diabetic complications. Differential inhibition of AKR1B1 has been proposed to counteract the damaging effects linked to the activity of the enzyme while preserving its detoxifying ability. Here, we show that epigallocatechin gallate (EGCG), one of the most representative catechins present in green tea, acts as a differential inhibitor of human recombinant AKR1B1. A kinetic analysis of EGCG, and of its components, gallic acid (GA) and epigallocatechin (EGC) as inhibitors of the reduction of L-idose, 4-hydroxy2,3-nonenal (HNE), and 3-glutathionyl l-4-dihydroxynonanal (GSHNE) revealed for the compounds a different model of inhibition toward the different substrates. While EGCG preferentially inhibited L-idose and GSHNE reduction with respect to HNE, gallic acid, which was still active in inhibiting the reduction of the sugar, was less active in inhibiting HNE and GSHNE reduction. EGC was found to be less efficient as an inhibitor of AKR1B1 and devoid of any differential inhibitory action. A computational study defined different interactive modes for the three substrates on the AKR1B1 active site and suggested a rationale for the observed differential inhibition. A chromatographic fractionation of an alcoholic green tea extract revealed that, besides EGCG and GA, other components may exhibit the differential inhibition of AKR1B1. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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19 pages, 6931 KiB

Open AccessArticle

Triterpenic Acids as Non-Competitive α-Glucosidase Inhibitors from Boswellia elongata with Structure-Activity Relationship: In Vitro and In Silico Studies

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Biomolecules 2020, 10(5), 751; https://doi.org/10.3390/biom10050751 - 12 May 2020

Cited by 31 | Viewed by 3255

Abstract

Fourteen triterpene acids, viz., three tirucallane-type (1–3), eight ursane-type (4–11), two oleanane-type (12, 13) and one lupane type (21), along with boswellic aldehyde (14), α-amyrine (15), [...] Read more.

Fourteen triterpene acids, viz., three tirucallane-type (1–3), eight ursane-type (4–11), two oleanane-type (12, 13) and one lupane type (21), along with boswellic aldehyde (14), α-amyrine (15), epi-amyrine (16), straight chain acid (17), sesquiterpene (19) and two cembrane-type diterpenes (18, 20) were isolated, first time, from the methanol extract of Boswellia elongata resin. Compound (1) was isolated for first time as a natural product, while the remaining compounds (2‒21) were reported for first time from B. elongata. The structures of all compounds were confirmed by advanced spectroscopic techniques including mass spectrometry and also by comparison with the reported literature. Eight compounds (1–5, 11, 19 and 20) were further screened for in vitro α-glucosidase inhibitory activity. Compounds 3–5 and 11 showed significant activity against α-glucosidase with IC₅₀ values ranging from 9.9–56.8 μM. Compound 4 (IC₅₀ = 9.9 ± 0.48 μM) demonstrated higher inhibition followed by 11 (IC₅₀ = 14.9 ± 1.31 μM), 5 (IC₅₀ = 20.9 ± 0.05 μM) and 3 (IC₅₀ = 56.8 ± 1.30 μM), indicating that carboxylic acid play a key role in α-glucosidase inhibition. Kinetics studies on the active compounds 3–5 and 11 were carried out to investigate their mechanism (mode of inhibition and dissociation constants K_i). All compounds were found to be non-competitive inhibitors with K_i values in the range of 7.05 ± 0.17–51.15 ± 0.25 µM. Moreover, in silico docking was performed to search the allosteric hotspot for ligand binding which is targeted by our active compounds investigates the binding mode of active compounds and it was identified that compounds preferentially bind in the allosteric binding sites of α-glucosidase. The results obtained from docking study suggested that the carboxylic group is responsible for their biologic activities. Furthermore, the α-glucosidase inhibitory potential of the active compounds is reported here for the first time. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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21 pages, 4835 KiB

Open AccessArticle

Assessment of the Pharmacological Properties and Phytochemical Profile of Bruguiera gymnorhiza (L.) Lam Using In Vitro Studies, In Silico Docking, and Multivariate Analysis

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Nabeelah Bibi Sadeer

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Kouadio Ibrahime Sinan

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Kannan R. R. Rengasamy

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Mohamad Fawzi Mahomoodally

Biomolecules 2020, 10(5), 731; https://doi.org/10.3390/biom10050731 - 07 May 2020

Cited by 18 | Viewed by 2986

Abstract

Bruguiera gymnorhiza (L.) Lam. is claimed to effectively manage a number of ailments including diabetes and associated complications. Nonetheless, no attempt has been made to delineate its pharmacological propensities and phytochemical profile. This study was designed to appraise the antioxidant and enzymatic inhibitory [...] Read more.

Bruguiera gymnorhiza (L.) Lam. is claimed to effectively manage a number of ailments including diabetes and associated complications. Nonetheless, no attempt has been made to delineate its pharmacological propensities and phytochemical profile. This study was designed to appraise the antioxidant and enzymatic inhibitory properties relevant to the management of diabetes mellitus, obesity, and neurodegenerative and skin disorders. A combination of colorimetric assays and ultra-high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) were applied for the phytochemical screening of leaf, root, twig, and fruit extracts (methanol and ethyl acetate). In vitro antioxidant evaluations were via radical scavenging abilities (DPPH, ABTS), reducing potential (FRAP, CUPRAC), chelating power, and total antioxidant capacity (phosphomolybdenum). Seven key metabolic enzymes (α-amylase, α-glucosidase, tyrosinase, elastase, lipase, AChE, and BChE) were targeted to determine the inhibitory effects. Multivariate and in silico docking analysis were performed on collected data. Methanolic fruit extract yielded the highest total phenolic, tannin, and triterpenoid contents (174.18 ± 4.27 mg GAE/g, 176.24 ± 3.10 mg CE/g, 63.11 ± 3.27 mg OAE/g, respectively); significantly depressed tyrosinase, elastase, and α-amylase activities (155.35 ± 0.29 mg KAE/g, 4.56 ± 0.10 mg CAE/g, 1.00 ± 0.05 mmol ACAE/g, accordingly); and harboured the most potent antioxidant capacities with DPPH, CUPRAC, FRAP (492.62 ± 5.31, 961.46 ± 11.18, 552.49 ± 8.71 mg TE/g, respectively), and phosphomolybdenum (4.17 ± 0.31 mmol TE/g) assays. Multivariate analysis suggested that the type of solvents used influenced the biological activities more compared to plant parts. Docking analysis showed that azelaic acid binds with tyrosinase by Van der Waals and conventional hydrogen bonds. We anticipate that the present study may establish baseline data on this halophyte that could open new avenues for the development of biomedicine. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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24 pages, 9874 KiB

Open AccessArticle

Green Synthesis of Gold Nanoparticles Capped with Procyanidins from Leucosidea sericea as Potential Antidiabetic and Antioxidant Agents

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Christopher N. Cupido

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Ahmed A. Hussein

Biomolecules 2020, 10(3), 452; https://doi.org/10.3390/biom10030452 - 13 Mar 2020

Cited by 64 | Viewed by 4609

Abstract

In this study, procyanidins fractions of dimers and trimers (F1–F2) from the Leucosidea sericea total extract (LSTE) were investigated for their chemical constituents. The total extract and the procyanidins were employed in the synthesis of gold nanoparticles (Au NPs) and fully characterized. Au [...] Read more.

In this study, procyanidins fractions of dimers and trimers (F1–F2) from the Leucosidea sericea total extract (LSTE) were investigated for their chemical constituents. The total extract and the procyanidins were employed in the synthesis of gold nanoparticles (Au NPs) and fully characterized. Au NPs of 6, 24 and 21 nm were obtained using LSTE, F1 and F2 respectively. Zeta potential and in vitro stability studies confirmed the stability of the particles. The enzymatic activity of LSTE, F1, F2 and their corresponding Au NPs showed strong inhibitory alpha-amylase activity where F1 Au NPs demonstrated the highest with IC₅₀ of 1.88 µg/mL. On the other hand, F2 Au NPs displayed the strongest alpha-glucosidase activity at 4.5 µg/mL. F2 and F2 Au NPs also demonstrated the highest antioxidant activity, 1834.0 ± 4.7 μM AAE/g and 1521.9 ± 3.0 μM TE/g respectively. The study revealed not only the ability of procyanidins dimers (F1 and F2) in forming biostable and bioactive Au NPs but also, a significant enhancement of the natural products activities, which could improve the smart delivery in future biomedical applications. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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16 pages, 4883 KiB

Open AccessArticle

Phytochemicals in Garlic Extract Inhibit Therapeutic Enzyme DPP-4 and Induce Skeletal Muscle Cell Proliferation: A Possible Mechanism of Action to Benefit the Treatment of Diabetes Mellitus

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Poonam Kalhotra

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Veera C.S.R. Chittepu

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Guillermo Osorio-Revilla

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Tzayhri Gallardo-Velazquez

Biomolecules 2020, 10(2), 305; https://doi.org/10.3390/biom10020305 - 14 Feb 2020

Cited by 33 | Viewed by 6287

Abstract

Diabetes mellitus is a severe health problem in Mexico, and its prevalence is increasing exponentially every year. Recently, DPP-4 (dipeptidyl peptidase-4) inhibitors have become attractive oral anti-hyperglycemic agents to reduce the pathology of diabetes. Gliptin’s family, such as sitagliptin, vildagliptin, and alogliptin, are [...] Read more.

Diabetes mellitus is a severe health problem in Mexico, and its prevalence is increasing exponentially every year. Recently, DPP-4 (dipeptidyl peptidase-4) inhibitors have become attractive oral anti-hyperglycemic agents to reduce the pathology of diabetes. Gliptin’s family, such as sitagliptin, vildagliptin, and alogliptin, are in clinical use to treat diabetes mellitus but possess side effects. Therefore, there is a specific need to look for new therapeutic scaffolds (biomolecules). Garlic bulb is widely used as a traditional remedy for the treatment of diabetes. The garlic extracts are scientifically proven to control glucose levels in patients with diabetes, despite the unknown mechanism of action. The aim of the study is to investigate the antidiabetic effects of ultrasonication assisted garlic bulb extract. To achieve this, in-vitro assays such as DPP-4 inhibitory and antioxidant activities were investigated. Further, functional group analysis using FTIR and identification of phytochemicals using mass spectrometry analysis was performed. The results showed that 70.9 µg/mL of garlic bulb extract inhibited 50% DPP-4 activity. On top of that, the garlic extract exhibited a 20% scavenging activity, equivalent to 10 µg/mL of ascorbic acid. Molecular docking simulations on identified phytochemicals using mass spectrometry revealed their potential binding at the DPP-4 druggable region, and therefore the possible DPP-4 inhibition mechanism. These results suggest that prepared garlic extract contains phytochemicals that inhibit DPP-4 and have antioxidant activity. Also, the prepared extract induces skeletal muscle cell proliferation that demonstrates the antidiabetic effect and its possible mechanism of action. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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24 pages, 4605 KiB

Open AccessArticle

Discrimination of Naturally-Occurring 2-Arylbenzofurans as Cyclooxygenase-2 Inhibitors: Insights into the Binding Mode and Enzymatic Inhibitory Activity

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Ericsson Coy-Barrera

Biomolecules 2020, 10(2), 176; https://doi.org/10.3390/biom10020176 - 23 Jan 2020

Cited by 10 | Viewed by 2562

Abstract

2-arylbenzofuran-containing compounds are chemical entities that can be naturally produced by several organisms. A wide-range of activities is described for several compounds of this kind and they are, therefore, valuable moieties for a lead finding from nature. Although there are in-vitro data about [...] Read more.

2-arylbenzofuran-containing compounds are chemical entities that can be naturally produced by several organisms. A wide-range of activities is described for several compounds of this kind and they are, therefore, valuable moieties for a lead finding from nature. Although there are in-vitro data about the activity of 2-arylbenzofuran-related compounds against cyclooxygenase (COX) enzymes, the molecular level of these COX-inhibiting constituents had not been deeply explored. Thus, 58 2-arylbenzofurans were initially screened through molecular docking within the active site of nine COX-2 crystal structures. The resulting docking scores were statistically analyzed and good reproducibility and convergence were found to discriminate the best-docked compounds. Discriminated compounds exhibited the best performance in molecular dynamics simulations as well as the most-favorable binding energies and the lowest in-vitro IC₅₀ values for COX-2 inhibition. A three-dimensional quantitative activity-structure relationship (3D-QSAR) was also demonstrated, which showed some crucial structural requirements for enhanced enzyme inhibition. Therefore, four hits are proposed as lead structures for the development of COX-2 inhibitors based on 2-arylbenzofurans in further studies. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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19 pages, 3116 KiB

Open AccessArticle

Alpha-Amylase and Alpha-Glucosidase Enzyme Inhibition and Antioxidant Potential of 3-Oxolupenal and Katononic Acid Isolated from Nuxia oppositifolia

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Valentina Razmovski-Naumovski

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Mohammed S. Alqahtani

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Rabab A. El Dib

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Mohamed F. AlAjmi

Biomolecules 2020, 10(1), 61; https://doi.org/10.3390/biom10010061 - 30 Dec 2019

Cited by 112 | Viewed by 8240

Abstract

Nuxia oppositifolia is traditionally used in diabetes treatment in many Arabian countries; however, scientific evidence is lacking. Hence, the present study explored the antidiabetic and antioxidant activities of the plant extracts and their purified compounds. The methanolic crude extract of N. oppositifolia was [...] Read more.

Nuxia oppositifolia is traditionally used in diabetes treatment in many Arabian countries; however, scientific evidence is lacking. Hence, the present study explored the antidiabetic and antioxidant activities of the plant extracts and their purified compounds. The methanolic crude extract of N. oppositifolia was partitioned using a two-solvent system. The n-hexane fraction was purified by silica gel column chromatography to yield several compounds including katononic acid and 3-oxolupenal. Antidiabetic activities were assessed by α-amylase and α-glucosidase enzyme inhibition. Antioxidant capacities were examined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) scavenging assays. Further, the interaction between enzymes (α-amylase and α-glucosidase) and ligands (3-oxolupenal and katononic acid) was followed by fluorescence quenching and molecular docking studies. 3-oxolupenal and katononic acid showed IC₅₀ values of 46.2 μg/mL (101.6 µM) and 52.4 μg/mL (119.3 µM), respectively against the amylase inhibition. 3-oxolupenal (62.3 µg/mL or 141.9 μM) exhibited more potent inhibition against α-glucosidases compared to katononic acid (88.6 µg/mL or 194.8 μM). In terms of antioxidant activity, the relatively polar crude extract and n-butanol fraction showed the greatest DPPH and ABTS scavenging activity. However, the antioxidant activities of the purified compounds were in the low to moderate range. Molecular docking studies confirmed that 3-oxolupenal and katononic acid interacted strongly with the active site residues of both α-amylase and α-glucosidase. Fluorescence quenching results also suggest that 3-oxolupenal and katononic acid have a good affinity towards both α-amylase and α-glucosidase enzymes. This study provides preliminary data for the plant’s use in the treatment of type 2 diabetes mellitus. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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11 pages, 2169 KiB

Open AccessArticle

Glucose Uptake Stimulatory and PTP1B Inhibitory Activities of Pimarane Diterpenes from Orthosiphon stamineus Benth

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Biomolecules 2019, 9(12), 859; https://doi.org/10.3390/biom9120859 - 11 Dec 2019

Cited by 11 | Viewed by 3520

Abstract

Seven pimarane diterpenes (1–7) were isolated from Orthosiphon stamineus Benth. by assay-guided isolation. All of the isolates possessed a 2-deoxy-2-((7-nitro-2,1,3-benzoxadiazol-4-yl)amino)-d-glucose uptake effect in 3T3-L1 adipocytes at concentrations of 5 and 10 μM. Most of them showed potent [...] Read more.

Seven pimarane diterpenes (1–7) were isolated from Orthosiphon stamineus Benth. by assay-guided isolation. All of the isolates possessed a 2-deoxy-2-((7-nitro-2,1,3-benzoxadiazol-4-yl)amino)-d-glucose uptake effect in 3T3-L1 adipocytes at concentrations of 5 and 10 μM. Most of them showed potent inhibition against protein tyrosine phosphatase 1B with IC₅₀ values ranging from 0.33 to 9.84 μM. In the kinetic study, all inhibition types were exposed for the examined potencies, including mixed-competitive (1), non-competitives (3 and 5), competitive (6), and uncompetitive (7). The results suggested that O. stamineus and its pimarane diterpenes might exert the hypoglycemic effect via the insulin signaling pathway targeting inhibition of protein tyrosine phosphatase 1B (PTP1B) activity. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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14 pages, 3255 KiB

Open AccessArticle

A Novel Kunitzin-Like Trypsin Inhibitor Isolated from Defensive Skin Secretion of Odorrana versabilis

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Biomolecules 2019, 9(7), 254; https://doi.org/10.3390/biom9070254 - 28 Jun 2019

Cited by 6 | Viewed by 2599

Abstract

Protease inhibitors that were identified from amphibian skin secretions with low molecular weights and potent inhibitory activity were thought to be potential candidates for novel peptide drugs. Here, a novel peptide with trypsin inhibitory activity was found in the skin secretion of the [...] Read more.

Protease inhibitors that were identified from amphibian skin secretions with low molecular weights and potent inhibitory activity were thought to be potential candidates for novel peptide drugs. Here, a novel peptide with trypsin inhibitory activity was found in the skin secretion of the Chinese bamboo leaf odorous frog, Odorrana versabilis. Based on the sequence alignments of sequencing results, the novel peptide (ALKYPFRCKAAFC) was named as Kunitzin-OV. The synthetic replicate of Kunitzin-OV was subjected to a series of functional assays, and it exhibited a trypsin inhibitory activity with a Ki value of 3.042 µM, whereas, when Lys-9 at P1 position was substituted by Phe, trypsin inhibitory activity was undetected and the chymotrypsin inhibitory activity was optimized with a Ki value of 2.874 µM. However, its protease-binding loop was catabolized by trypsin during the trypsin cleavage test. In conclusion, Kunizin-OV is a novel peptide with trypsin inhibitory activity as a member of kunitzins, which is a non-typical Kunitz-like trypsin inhibitor with a highly conserved reactive site (K-A) and quite a short sequence. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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30 pages, 2592 KiB

Open AccessReview

Compounds from Natural Sources as Protein Kinase Inhibitors

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Andrea Baier

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Ryszard Szyszka

Biomolecules 2020, 10(11), 1546; https://doi.org/10.3390/biom10111546 - 12 Nov 2020

Cited by 30 | Viewed by 7280

Abstract

The advantage of natural compounds is their lower number of side-effects when compared to most synthetic substances. Therefore, over the past several decades, the interest in naturally occurring compounds is increasing in the search for new potent drugs. Natural compounds are playing an [...] Read more.

The advantage of natural compounds is their lower number of side-effects when compared to most synthetic substances. Therefore, over the past several decades, the interest in naturally occurring compounds is increasing in the search for new potent drugs. Natural compounds are playing an important role as a starting point when developing new selective compounds against different diseases. Protein kinases play a huge role in several diseases, like cancers, neurodegenerative diseases, microbial infections, or inflammations. In this review, we give a comprehensive view of natural compounds, which are/were the parent compounds in the development of more potent substances using computational analysis and SAR studies. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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30 pages, 12454 KiB

Open AccessReview

Natural Products Attenuating Biosynthesis, Processing, and Activity of Ras Oncoproteins: State of the Art and Future Perspectives

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Biomolecules 2020, 10(11), 1535; https://doi.org/10.3390/biom10111535 - 10 Nov 2020

Cited by 7 | Viewed by 2832

Abstract

RAS genes encode signaling proteins, which, in mammalian cells, act as molecular switches regulating critical cellular processes as proliferation, growth, differentiation, survival, motility, and metabolism in response to specific stimuli. Deregulation of Ras functions has a high impact on human health: gain-of-function point [...] Read more.

RAS genes encode signaling proteins, which, in mammalian cells, act as molecular switches regulating critical cellular processes as proliferation, growth, differentiation, survival, motility, and metabolism in response to specific stimuli. Deregulation of Ras functions has a high impact on human health: gain-of-function point mutations in RAS genes are found in some developmental disorders and thirty percent of all human cancers, including the deadliest. For this reason, the pathogenic Ras variants represent important clinical targets against which to develop novel, effective, and possibly selective pharmacological inhibitors. Natural products represent a virtually unlimited resource of structurally different compounds from which one could draw on for this purpose, given the improvements in isolation and screening of active molecules from complex sources. After a summary of Ras proteins molecular and regulatory features and Ras-dependent pathways relevant for drug development, we point out the most promising inhibitory approaches, the known druggable sites of wild-type and oncogenic Ras mutants, and describe the known natural compounds capable of attenuating Ras signaling. Finally, we highlight critical issues and perspectives for the future selection of potential Ras inhibitors from natural sources. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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